Bio

Academic Appointments


Honors & Awards


  • Endowed Thomas C and Joan M Merigan chair in Medicine, Stanford University (2008)
  • Festschift with publication(J. of Inf. Dis. 162,Supp. 1,2006), Sponsored by former students (2004)
  • George E. and Lucy Becker Professor of Medicine, Stanford University (!980-2006)
  • One of "250 Most Highly Cited Scientists in Clinical Medicine over 20 years,1983-2001", Institute of Scientific Information (2004)
  • Elected to Honorary Membership, International Society for Interferon and Cytokine Research (2001)
  • Establishment of Annual Thomas C. Merigan, Jr. Endowed Lectureship in I.D., Stanford Medical School, Funded by Friends and Former Fellows (1994)
  • "Making A Difference" Award, Hollis-Eden Corporation, San Diego, CA (2001)
  • Elected Member, Institute of Medicine,National Academy of Sciences (!980)
  • Elected Fellow, American Association for the Advancement of Science (1995)
  • Maxwell Finland Lectureship Award, Infectious Diseases Society of America (1988)
  • MERIT [Method to Extend Research in Time]Award, National Institutes of Allergy & Infectious Diseases (1988)
  • Identified as one of "The One Thousand Most Cited Contemporary Scientists", Institute for Scientific Information (1973-1988)
  • Borden Award for Outstanding Research, American Associaion of Medical Colleges (1973)
  • John Simon Guggenheim Memorial Fellowship Award, John Simon Guggenheim Foundation (1972)

Research & Scholarship

Current Research and Scholarly Interests


I am now emeritus and only participate in university activities through advising my former trainees who have joined the faculty.

Teaching

Graduate and Fellowship Programs


Publications

Journal Articles


  • In vitro HIV-1 evolution in response to triple reverse transcriptase inhibitors & in silico phenotypic analysis. PloS one Rath, B. A., Yousef, K. P., Katzenstein, D. K., Shafer, R. W., Schütte, C., von Kleist, M., Merigan, T. C. 2013; 8 (4)

    Abstract

    Effectiveness of ART regimens strongly depends upon complex interactions between the selective pressure of drugs and the evolution of mutations that allow or restrict drug resistance.Four clinical isolates from NRTI-exposed, NNRTI-naive subjects were passaged in increasing concentrations of NVP in combination with 1 µM 3 TC and 2 µM ADV to assess selective pressures of multi-drug treatment. A novel parameter inference procedure, based on a stochastic viral growth model, was used to estimate phenotypic resistance and fitness from in vitro combination passage experiments.Newly developed mathematical methods estimated key phenotypic parameters of mutations arising through selective pressure exerted by 3 TC and NVP. Concentrations of 1 µM 3 TC maintained the M184V mutation, which was associated with intrinsic fitness deficits. Increasing NVP concentrations selected major NNRTI resistance mutations. The evolutionary pathway of NVP resistance was highly dependent on the viral genetic background, epistasis as well as stochasticity. Parameter estimation indicated that the previously unrecognized mutation L228Q was associated with NVP resistance in some isolates.Serial passage of viruses in the presence of multiple drugs may resemble the selection of mutations observed among treated individuals and populations in vivo and indicate evolutionary preferences and restrictions. Phenotypic resistance estimated here "in silico" from in vitro passage experiments agreed well with previous knowledge, suggesting that the unique combination of "wet-" and "dry-lab" experimentation may improve our understanding of HIV-1 resistance evolution in the future.

    View details for DOI 10.1371/journal.pone.0061102

    View details for PubMedID 23613794

  • Persistence versus Reversion of 3TC Resistance in HIV-1 Determine the Rate of Emergence of NVP Resistance VIRUSES-BASEL Rath, B. A., Olshen, R. A., Halpern, J., Merigan, T. C. 2012; 4 (8): 1212-1234

    Abstract

    When HIV-1 is exposed to lamivudine (3TC) at inhibitory concentrations, resistant variants carrying the reverse transcriptase (RT) substitution M184V emerge rapidly. This substitution confers high-level 3TC resistance and increased RT fidelity. We established a novel in vitro system to study the effect of starting nevirapine (NVP) in 3TC-resistant/NNRTI-naïve clinical isolates, and the impact of maintaining versus dropping 3TC pressure in this setting. Because M184V mutant HIV-1 seems hypersusceptible to adefovir (ADV), we also tested the effect of ADV pressure on the same isolates. We draw four conclusions from our experiments simulating combination therapy in vitro. (1) The presence of low-dose (1 ?M) 3TC prevented reversal to wild-type from an M184V mutant background. (2) Adding low-dose 3TC in the presence of NVP delayed the selection of NVP-associated mutations. (3) The presence of ADV, in addition to NVP, led to more rapid reversal to wild-type at position 184 than NVP alone. (4) ADV plus NVP selected for greater numbers of mutations than NVP alone. Inference about the "selection of mutation" is based on two statistical models, one at the viral level, more telling, and the other at the level of predominance of mutation within a population. Multidrug pressure experiments lend understanding to mechanisms of HIV resistance as they bear upon new treatment strategies.

    View details for DOI 10.3390/v4081212

    View details for Web of Science ID 000308213000003

    View details for PubMedID 23012621

  • Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34(+) cells NATURE MEDICINE Mitsuyasu, R. T., Merigan, T. C., Carr, A., Zack, J. A., Winters, M. A., Workman, C., Bloch, M., Lalezari, J., Becker, S., Thornton, L., Akil, B., Khanlou, H., Finlayson, R., McFarlane, R., Smith, D. E., Garsia, R., Ma, D., Law, M., Murray, J. M., von Kalle, C., Ely, J. A., Patino, S. M., Knop, A. E., Wong, P., Todd, A. V., Haughton, M., Fuery, C., Macpherson, J. L., Symonds, G. P., Evans, L. A., Pond, S. M., Cooper, D. A. 2009; 15 (3): 285-292

    Abstract

    Gene transfer has potential as a once-only treatment that reduces viral load, preserves the immune system and avoids lifetime highly active antiretroviral therapy. This study, which is to our knowledge the first randomized, double-blind, placebo-controlled, phase 2 cell-delivered gene transfer clinical trial, was conducted in 74 HIV-1-infected adults who received a tat-vpr-specific anti-HIV ribozyme (OZ1) or placebo delivered in autologous CD34+ hematopoietic progenitor cells. There were no OZ1-related adverse events. There was no statistically significant difference in viral load between the OZ1 and placebo group at the primary end point (average at weeks 47 and 48), but time-weighted areas under the curve from weeks 40-48 and 40-100 were significantly lower in the OZ1 group. Throughout the 100 weeks, CD4+ lymphocyte counts were higher in the OZ1 group. This study indicates that cell-delivered gene transfer is safe and biologically active in individuals with HIV and can be developed as a conventional therapeutic product.

    View details for DOI 10.1038/nm.1932

    View details for Web of Science ID 000263914000028

    View details for PubMedID 19219022

  • Multilocus genetic interactions and response to efavirenz-containing regimens: an Adult AIDS Clinical Trials Group study PHARMACOGENETICS AND GENOMICS Motsinger, A. A., Ritchie, M. D., Shafer, R. W., Robbins, G. K., Morse, G. D., Labbe, L., Wilkinson, G. R., Clifford, D. B., D'Aquila, R. T., Johnson, V. A., Pollard, R. B., Merigan, T. C., Hirsch, M. S., Donahue, J. P., Kim, R. B., Haas, D. W. 2006; 16 (11): 837-845

    Abstract

    For the HIV-1 reverse transcriptase inhibitor efavirenz, variant drug transporter gene ABCB1 may predict virologic response but not plasma efavirenz exposure. Conversely, variant drug metabolizing enzyme gene CYP2B6 predicts greater plasma efavirenz exposure but not virologic response. We examined whether long-term responses to efavirenz, and/or plasma efavirenz exposure, are better predicted by multilocus genetic interactions than by individual polymorphisms.We studied antiretroviral-naïve study participants randomized to receive efavirenz (with or without nelfinavir) plus two nucleoside analogues in study ACTG 384, and who had DNA available for analysis. Participants were followed up for up to 3 years. Nine single nucleotide polymorphisms in ABCB1, CYP2B6, CYP3A4, CYP3A5 and CYP2C19 were identified. Gene-gene interactions were identified using multifactor dimensionality reduction.Among 340 efavirenz recipients, higher efavirenz AUC24 h values were associated with a single locus model involving CYP2B6 516G>T (73% accuracy; P<0.001). This was also the best model among blacks (69% accuracy; P<0.001), whereas among whites the best model involved a gene-gene interaction between CYP2B6 516G>T and ABCB1 2677G>T (82% accuracy, P<0.001). Among 155 participants who received efavirenz without nelfinavir, virologic failure was associated with a two-locus interaction between ABCB1 2677G>T and CYP2B6 516G>T (65% accuracy, P<0.001). Toxicity failure was best predicted by an interaction between ABCB1 2677G>T and ABCB1 3435C>T (71% accuracy, P<0.001).Multilocus genetic interactions between variant drug metabolism and transporter genes may predict efavirenz pharmacokinetics and treatment responses. This finding may have implications for better individualizing antiretroviral therapy.

    View details for Web of Science ID 000241971500009

    View details for PubMedID 17047492

  • Effect of baseline- and treatment-related factors on immunologic recovery after initiation of antiretroviral therapy in HIV-1-positive subjects: Results from ACTG 384 JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Gandhi, R. T., Spritzler, J., Chan, E., Asmuth, D. M., Rodriguez, B., Merigan, T. C., Hirsch, M. S., Shafer, R. W., Robbins, G. K., Pollard, R. B. 2006; 42 (4): 426-434

    Abstract

    To assess the effect of baseline- and treatment-related factors on immunologic recovery after initiation of antiretroviral therapy (ART).Nine hundred eighty antiretroviral-naive HIV-1+ subjects were randomized to start stavudine/didanosine or zidovudine/lamivudine with nelfinavir, efavirenz, or both nelfinavir and efavirenz.Greater CD4 cell recovery was associated with age of 40 years or younger, female sex, higher baseline naive/memory CD4 cell ratio, higher baseline virus load (VL), and virologic suppression (VS). Most subjects who maintained an undetectable VL had a substantial increase in CD4 cell count, but 13% of the subjects did not, even after 3 years of VS. Persistent T-cell activation was associated with lower CD4 cell recovery, even in subjects who achieved VS. Initial treatment assignment did not affect total CD4 cell recovery, naive/memory CD4 cell reconstitution, or decline in T-cell activation. In addition to CD4 cell recovery, B-cell counts rose substantially after ART initiation.In this large randomized trial, younger age, female sex, higher naive/memory CD4 cell ratio, higher baseline VL, and VS were associated with greater CD4 cell increase, whereas persistent T-cell activation was associated with impaired CD4 cell recovery after ART initiation. Initial treatment assignment did not affect CD4 cell reconstitution.

    View details for Web of Science ID 000239129100006

    View details for PubMedID 16810109

  • "Wide-open" 1.3 angstrom structure of a multidrug-resistant HIV-1 protease as a drug target STRUCTURE Martin, P., Vickrey, J. F., Proteasa, G., Jimenez, Y. L., Wawrzak, Z., Winters, M. A., Merigan, T. C., Kovari, L. C. 2005; 13 (12): 1887-1895

    Abstract

    This report examines structural changes in a highly mutated, clinical multidrug-resistant HIV-1 protease, and the crystal structure has been solved to 1.3 A resolution in the absence of any inhibitor. This protease variant contains codon mutations at positions 10, 36, 46, 54, 62, 63, 71, 82, 84, and 90 that confer resistance to protease inhibitors. Major differences between the wild-type and the variant include a structural change initiated by the M36V mutation and amplified by additional mutations in the flaps of the protease, resulting in a "wide-open" structure that represents an opening that is 8 A wider than the "open" structure of the wild-type protease. A second structural change is triggered by the L90M mutation that results in reshaping the 23-32 segment. A third key structural change of the protease is due to the mutations from longer to shorter amino acid side chains at positions 82 and 84.

    View details for DOI 10.1016/j.str.2005.11.005

    View details for Web of Science ID 000234286900019

    View details for PubMedID 16338417

  • Pharmacogenetics of long-term responses to antiretroviral regimens containing efavirenz and/or nelfinavir: An adult AIDS clinical trials group study JOURNAL OF INFECTIOUS DISEASES Haas, D. W., Smeaton, L. M., Shafer, R. W., Robbins, G. K., Morse, G. D., Labbe, L., Wilkinson, G. R., Clifford, D. B., D'Aquila, R. T., De Gruttola, V., Pollard, R. B., Merigan, T. C., Hirsch, M. S., George, A. L., Donahue, J. P., Kim, R. B. 2005; 192 (11): 1931-1942

    Abstract

    Efavirenz and nelfinavir are metabolized by cytochrome P-450 (CYP) 2B6 and CYP2C19, respectively, with some involvement by CYP3A. Nelfinavir is a substrate for P-glycoprotein, which is encoded by MDR1. The present study examined associations between genetic variants and long-term responses to treatment.Adult AIDS Clinical Trials Group study 384 randomized antiretroviral-naive subjects to receive efavirenz and/or nelfinavir plus 2 nucleoside analogues, with follow-up lasting up to 3 years. Population pharmacokinetics were estimated from a nonlinear mixed-effects model. Polymorphisms in CYP2B6, CYP2C19, CYP3A4, CYP3A5, and MDR1 were characterized.The 504 participants in the genetic study included 340 efavirenz recipients and 348 nelfinavir recipients (184 of the 504 participants received both efavirenz and nelfinavir). Of the participants, 49% were white, 31% were black, and 19% were Hispanic. Plasma exposure to efavirenz and nelfinavir in each population was significantly associated with the polymorphisms CYP2B6 516G-->T and CYP2C19 681G-->A, respectively. Among efavirenz recipients, the MDR1 position 3435 TT genotype was associated with decreased likelihood of virologic failure and decreased emergence of efavirenz-resistant virus but not with plasma efavirenz exposure. Among nelfinavir recipients, a trend toward decreased virologic failure was associated with the polymorphism CYP2C19 681G-->A.Genetic variants predict plasma exposure to efavirenz and nelfinavir, and they may predict virologic failure and/or emergence of drug-resistant virus. These associations with treatment responses must be validated in other studies.

    View details for Web of Science ID 000233018200011

    View details for PubMedID 16267764

  • Pharmacokinetics of nelfinavir and efavirenz in antiretroviral-naive, human immunodeficiency virus-infected subjects when administered alone or in combination with nucleoside analog reverse transcriptase inhibitors ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Smith, P. F., Robbins, G. K., Shafer, R. W., Wu, H. L., Yu, S., Hirsch, M. S., Merigan, T. C., Park, J. G., Forrest, A., Fischl, M. A., Morse, G. D. 2005; 49 (8): 3558-3561

    Abstract

    Pharmacokinetic studies were conducted with human immunodeficiency virus-infected patients receiving efavirenz, nelfinavir, or both agents at weeks 4 and 32. Reductions of 25% and 45% were observed in the mean nelfinavir area under the concentration-time curve and minimum concentration of the drug in serum, and there was a 31% more rapid half-life for patients receiving both drugs compared to patients receiving nelfinavir alone. There were no significant differences in efavirenz pharmacokinetics.

    View details for DOI 10.1128/AAC.49.8.3558-3561.2005

    View details for Web of Science ID 000230950700074

    View details for PubMedID 16048984

  • Antiviral activity of lamivudine in salvage therapy for multidrug-resistant HIV-1 infection CLINICAL INFECTIOUS DISEASES Campbell, T. B., Shulman, N. S., Johnson, S. C., Zolopa, A. R., Young, R. K., Bushman, L., Fletcher, C. V., Lanier, E. R., Merigan, T. C., Kuritzkes, D. R. 2005; 41 (2): 236-242

    Abstract

    Maximum suppression of virus replication is often not achievable for persons infected with multidrug-resistant human immunodeficiency virus type 1 (HIV-1). Available data suggest that lamivudine contributes to partial viral suppression, despite the presence of M184V mutations and high-level phenotypic lamivudine resistance.Selective lamivudine withdrawal was studied in 6 subjects who had incomplete viral suppression during antiretroviral treatment for multidrug-resistant HIV-1 infection.Plasma levels of HIV-1 RNA increased to 0.5 log(10) copies/mL above baseline 6 weeks after the withdrawal of lamivudine treatment (P=.04), even though reversion of lamivudine resistance was not yet detected. Early increases in plasma levels of HIV-1 RNA after lamivudine withdrawal were associated with the presence of the T215Y/F mutation and broad phenotypic resistance to nucleoside reverse-transcriptase inhibitors at baseline. Genotypic and phenotypic reversion of lamivudine resistance was detected in 4 subjects 8-14 weeks after withdrawal of lamivudine therapy. The duration of lamivudine withdrawal ranged from 8 to 22 weeks; all subjects resumed lamivudine treatment. Plasma levels of HIV-1 RNA were 0.6 log(10) copies/mL above baseline (P=.03) when lamivudine therapy was resumed. After the resumption of lamivudine treatment, plasma HIV RNA levels decreased to baseline levels in 3 subjects but remained elevated in 3 subjects who had evolution of increased antiretroviral drug resistance during the period of lamivudine withdrawal. Safety concerns raised by this latter finding led to permanent closure of the study.In select cases of multidrug-resistant HIV-1 infection, lamivudine contributes to suppression of HIV-1 replication, despite the presence of M184V mutations and lamivudine resistance.

    View details for Web of Science ID 000229890800016

    View details for PubMedID 15983922

  • Insertions in the human immunodeficiency virus type 1 protease and reverse transcriptase genes: Clinical impact and molecular mechanisms ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Winters, M. A., Merigan, T. C. 2005; 49 (7): 2575-2582
  • Nonnucleoside reverse transcriptase inhibitor phenotypic hypersusceptibility can be demonstrated in different assays JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Shulman, N. S., Delgado, D., Bosch, R. J., Winters, M. A., Johnston, E., Shafer, R. W., Katzenstein, D. A., Merigan, T. C. 2005; 39 (1): 78-81

    Abstract

    HIV-1 isolates harboring multiple nucleoside reverse transcriptase inhibitor (NRTI) resistance mutations are more susceptible ("hypersusceptible") to the nonnucleoside reverse transcriptase inhibitors (NNRTIs) than isolates lacking NRTI resistance mutations, but this has only been reported with a single-cycle replication phenotypic assay. In fact, there was a report that a commercial multicycle assay did not readily detect hypersusceptibility.To see whether NNRTI hypersusceptibility can be demonstrated in other types of phenotypic assays, including multicycle assays and enzyme inhibition assays.The susceptibility of HIV-1 clones derived from different patients in multicycle assays was tested in peripheral blood mononuclear cells (PBMCs) and in an established cell line. In addition, the reverse transcriptase (RT) of many of these clones was expressed and their susceptibility tested in an RT inhibition assay. Nevirapine and efavirenz susceptibilities were tested and compared with a control wild-type virus or RT.Hypersusceptibility to nevirapine and efavirenz was detected using each of the methods described above. R values correlating the other methods with single-cycle assay values were between 0.66 and 0.96. In addition to the high correlations, the different methods gave similar numeric results.NNRTI hypersusceptibility is readily seen in multicycle susceptibility assays and in enzyme inhibition assays.

    View details for Web of Science ID 000228812000011

    View details for PubMedID 15851917

  • New two-amino acid insertion near codon 70 of the HIV type 1 protease gene AIDS RESEARCH AND HUMAN RETROVIRUSES Winters, M. A., Kagan, R. M., HESELTINE, P. N., Merigan, T. C. 2005; 21 (4): 311-313

    Abstract

    A two-amino acid insertion near codon 70 of the HIV-1 protease gene was found in an individual failing protease inhibitor therapy. Susceptibility of this strain to protease inhibitors was similar to that of non-insert-containing strains with comparable resistance mutations and one or more other major PI mutations.

    View details for Web of Science ID 000229111000009

    View details for PubMedID 15943574

  • Rare one and two amino acid inserts adjacent to codon 103 of the HIV-1 reverse transcriptase (RT) affect susceptibility to non-nucleoside RT inhibitors ANTIVIRAL THERAPY Winters, M. A., Kagan, R. M., Kovari, L., HESELTINE, P. N., Merigan, T. C. 2005; 10 (2): 363-366

    Abstract

    HIV-1 strains that possess a one or two amino acid insert between codons 102 and 103 of the reverse transcriptase (RT) gene were identified in three HIV-1-infected individuals. Each strain also had one or more known mutations associated with nucleoside RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs). Recombinant viruses from these strains had reduced susceptibility to efavirenz and nevirapine, and homology modelling predicted a loss of binding contacts with efavirenz. Mutagenesis studies indicated that replication of insert-containing strains was dependent on RT gene mutations and polymorphisms that co-evolved with the insert. These results suggest that inserts in the NNRTI-binding pocket contribute to NNRTI resistance, but are tolerated only under specific genetic conditions.

    View details for Web of Science ID 000231962300020

    View details for PubMedID 15865232

  • Association of a novel human immunodeficiency virus type 1 protease substrate cleft mutation, L23I, with protease inhibitor therapy and in vitro drug resistance ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Johnston, E., Winters, M. A., Rhee, S. Y., Merigan, T. C., Schiffer, C. A., Shafer, R. W. 2004; 48 (12): 4864-4868

    Abstract

    We observed a previously uncharacterized mutation in the protease substrate cleft, L23I, in 31 of 4,303 persons undergoing human immunodeficiency virus type 1 genotypic resistance testing. In combination with V82I, L23I was associated with a sevenfold reduction in nelfinavir susceptibility and a decrease in replication capacity. In combination with other drug resistance mutations, L23I was associated with multidrug resistance and a compensatory increase in replication capacity.

    View details for DOI 10.1128/AAC.48.12.4864-4868.2004

    View details for Web of Science ID 000225474500052

    View details for PubMedID 15561868

  • Human immunodeficiency virus type 1 infection in Oman: Antiretroviral therapy and frequencies of drug resistance mutations AIDS RESEARCH AND HUMAN RETROVIRUSES Al Dhahry, S. H., Scrimgeour, E. M., Al Suwaid, A. R., Al Lawati, M. R., El Khatim, H. S., Al Kobaisi, M. F., Merigan, T. C. 2004; 20 (11): 1166-1172

    Abstract

    Highly active antiretroviral therapy (HAART), consisting mainly of two nucleoside reverse transcriptase inhibitors (NRTIs) and one protease inhibitor (PI), is offered to < 10% of HIV-infected subjects in Oman. The aims of the present study were to determine the frequency of resistance-associated mutations in these patients, and to assess the contribution of drug resistance to treatment outcome. Among 29 patients on HAART for > or =6 months, virological, failure was observed in 27 (93%). Genotypic analysis indicated that in five of these 27 patients, there were no mutations that confer resistance to reverse transcriptase inhibitors (RTIs). The genotypes of 17 other patients carried one or two RTI mutations, mainly the lamivudine-associated resistance mutation M184V. Three or more RTI mutations were found in only five (14.7%) patients with virological failure, including three patients on the nonnucleoside RTI efavirenz. Major PI mutations were infrequent, and were detected in seven (26%) of 27 patients failing HAART, mainly as single mutation at codons 82 or 90. In contrast, accessory mutations in the protease gene were present in all patients. However, there were significant differences in the prevalence of accessory mutations at codons 36 and 77 among clade B and non-B viruses. When genotypic data of this study were used to change therapy of seven patients whose isolates had multiple resistance mutations, adequate viral suppression was observed in five. Our results indicate that the high rate of treatment failure among patients in Oman is mainly due to factors other than resistance to antiretroviral drugs. These factors, which may include nonadherence to therapy and treatment interruptions, need to be investigated.

    View details for Web of Science ID 000225576400004

    View details for PubMedID 15588338

  • Increasing prevalence of HIV-1 reverse transcriptase mutation K65R correlates with tenofovir utilization ANTIVIRAL THERAPY Kagan, R. M., Merigan, T. C., Winters, M. A., HESELTINE, P. N. 2004; 9 (5): 827-828

    View details for Web of Science ID 000231615800023

    View details for PubMedID 15535422

  • Short-term safety and antiretroviral activity of T-1249, a second-generation fusion inhibitor of HIV JOURNAL OF INFECTIOUS DISEASES Eron, J. J., Gulick, R. M., Bartlett, J. A., Merigan, T., Arduino, R., Kilby, J. M., Yangco, B., Diers, A., Drobnes, C., DeMasi, R., Greenberg, M., Melby, T., Raskino, C., Rusnak, P., Zhang, Y., Spence, R., Miralles, G. D. 2004; 189 (6): 1075-1083

    Abstract

    T-1249 is a 39-aa synthetic peptide that inhibits fusion of human immunodeficiency virus (HIV) to the host target cell. A 14-day open-label, phase 1/2 dose-escalation monotherapy study of the safety and antiretroviral activity of T-1249 was performed on 115 HIV-1-infected adults. At baseline, the majority of the patients had advanced HIV disease (baseline median CD4(+) cell count, 57 cells/microL) and had extensive pretreatment (i.e., pre-T-1249) experience with antiretroviral medications (median, 11 antiretroviral drugs). Patients received T-1249 monotherapy by subcutaneous injection, for 14 days, at doses ranging from 6.25 to 192 mg/day. T-1249 was generally well tolerated, and no dose-limiting toxicity was identified. Injection-site reactions were the most commonly reported adverse event (57%). Dose-dependent decreases in plasma HIV-1 RNA load were observed; the median maximum change from baseline across dose groups ranged from -0.29 log(10) copies/mL (95% confidence interval [CI], -0.43 to -0.05 log(10) copies/mL) for the lowest dose to -1.96 log(10) copies/mL (95% CI, -2.02 to -1.37 copies/mL) for the highest dose. These results indicate that T-1249 is a potent new therapeutic agent for HIV-1 infection.

    View details for Web of Science ID 000220001100015

    View details for PubMedID 14999611

  • Crystal structures of a multidrug-resistant human immunodeficiency virus type 1 protease reveal an expanded active-site cavity JOURNAL OF VIROLOGY Logsdon, B. C., Vickrey, J. F., Martin, P., Proteasa, G., Koepke, J. I., Terlecky, S. R., Wawrzak, Z., Winters, M. A., Merigan, T. C., Kovari, L. C. 2004; 78 (6): 3123-3132

    Abstract

    The goal of this study was to use X-ray crystallography to investigate the structural basis of resistance to human immunodeficiency virus type 1 (HIV-1) protease inhibitors. We overexpressed, purified, and crystallized a multidrug-resistant (MDR) HIV-1 protease enzyme derived from a patient failing on several protease inhibitor-containing regimens. This HIV-1 variant contained codon mutations at positions 10, 36, 46, 54, 63, 71, 82, 84, and 90 that confer drug resistance to protease inhibitors. The 1.8-angstrom (A) crystal structure of this MDR patient isolate reveals an expanded active-site cavity. The active-site expansion includes position 82 and 84 mutations due to the alterations in the amino acid side chains from longer to shorter (e.g., V82A and I84V). The MDR isolate 769 protease "flaps" stay open wider, and the difference in the flap tip distances in the MDR 769 variant is 12 A. The MDR 769 protease crystal complexes with lopinavir and DMP450 reveal completely different binding modes. The network of interactions between the ligands and the MDR 769 protease is completely different from that seen with the wild-type protease-ligand complexes. The water molecule-forming hydrogen bonds bridging between the two flaps and either the substrate or the peptide-based inhibitor are lacking in the MDR 769 clinical isolate. The S1, S1', S3, and S3' pockets show expansion and conformational change. Surface plasmon resonance measurements with the MDR 769 protease indicate higher k(off) rates, resulting in a change of binding affinity. Surface plasmon resonance measurements provide k(on) and k(off) data (K(d) = k(off)/k(on)) to measure binding of the multidrug-resistant protease to various ligands. This MDR 769 protease represents a new antiviral target, presenting the possibility of designing novel inhibitors with activity against the open and expanded protease forms.

    View details for DOI 10.1128/JVI.78.6.3123-3132.2004

    View details for Web of Science ID 000220043100047

    View details for PubMedID 14990731

  • HIV type 1 genotypic resistance in a clinical database correlates with antiretroviral utilization AIDS RESEARCH AND HUMAN RETROVIRUSES Kagan, R., Winters, M., Merigan, T., Heseltine, P. 2004; 20 (1): 1-9

    Abstract

    We established a database of HIV-1 reverse transcriptase (RT) and protease (PR) sequences and mutations to monitor the prevalence of antiretroviral drug resistance and mutational patterns in clinical samples submitted for testing to a major U.S. reference laboratory. At the end of 1998, 80% of the clinical samples tested harbored HIV strains with genotypically predicted resistance to at least one antiretroviral (ARV) drug. By the third quarter of 2002, the frequency of genotypically predicted resistance declined to 65% of samples tested. The prevalence of both PR and nucleoside RT inhibitor resistance declined over this period, while an increase in resistance to nonnucleoside RT inhibitors was found. These genotypic results strongly correlated with a nationwide decrease in the prescription of PR and nucleoside RT inhibitors, and an increase in the prescription of nonnucleoside RT inhibitors over the time period. The increased number of strains that were genotypically sensitive to all classes of ARV probably indicates an increase in genotypic assay use in ARV-naive individuals, however, the trends and correlations in this data set were similar when evaluated after removal of genotypically sensitive strains. Continued monitoring of ARV resistance prevalence, patterns, and utilization trends in clinical databases provides insight into the evolving relationship between clinical practice and ARV resistance.

    View details for Web of Science ID 000188861700001

    View details for PubMedID 15000693

  • Granulocyte-macrophage colony-stimulating factor induces modest increases in plasma human immunodeficiency virus (HIV) type 1 RNA levels and CD4(+) lymphocyte counts in patients with uncontrolled HIV infection JOURNAL OF INFECTIOUS DISEASES Jacobson, J. M., Lederman, M. M., Spritzler, J., Valdez, H., Tebas, P., Skowron, G., Wang, R., Jackson, J. B., Fox, L., Landay, A., Gilbert, M. J., O'Neil, D., Bancroft, L., Al-Harthi, L., Jacobson, M. A., Merigan, T. C., Glesby, M. J. 2003; 188 (12): 1804-1814

    Abstract

    Studies have reported that plasma human immunodeficiency virus type 1 (HIV-1) RNA levels and CD4+ lymphocyte counts in HIV-infected patients improved after treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF).In AIDS Clinical Trials Group Protocol 5041, 116 patients were enrolled in a double-blind, randomized, placebo-controlled clinical trial of 16 weeks of 250 microg of GM-CSF administered subcutaneously 3 times/week, followed by open-label treatment for an additional 32 weeks. Patients had stable baseline plasma HIV-1 RNA levels of > or =1500 copies/mL and received constant antiretroviral regimens through at least the first 16 weeks of the study.After 16 weeks, the GM-CSF group tended to have greater, though clinically insignificant, increases in plasma HIV-1 RNA levels, compared with the placebo group (median change, +0.048 vs. -0.103 log copies/mL; P=.036, in a post hoc analysis). There were trends toward progressive modest increases in CD4+ lymphocyte counts with GM-CSF treatment at 16 weeks (median change, +14 vs. -6 cells/mm3; P=.06) and beyond.GM-CSF does not have an antiviral effect in patients with ongoing HIV replication but may increase CD4+ lymphocyte counts.

    View details for Web of Science ID 000187992700003

    View details for PubMedID 14673758

  • Comparison of four-drug regimens and pairs of sequential three-drug regimens as initial therapy for HIV-1 infection NEW ENGLAND JOURNAL OF MEDICINE Shafer, R. W., Smeaton, L. M., Robbins, G. K., De Gruttola, V., Snyder, S. W., D'Aquila, R. T., JOHNSON, V. A., Morse, G. D., Nokta, M. A., Martinez, A. I., Gripshover, B. M., Kaul, P., Haubrich, R., Swingle, M., McCarty, S. D., Vella, S., Hirsch, M. S., Merigan, T. C., Fischl, M., Pollard, R., Dube, M., Pettinelli, C., Delapenha, R., Putnam, B., Klebert, M., Testa, M., Chiesi, A., Tomino, C., Deeks, S., Nevin, T., Levin, J., French, V., Fennell, O., Stevens, M., Grosso, R., Dusak, B., Hodder, S., Tolson, J., Brothers, C., Leavitt, R., Manion, D., Ruiz, N., Morrisey, K., Becker, M., Quart, B., Jennings, C., Gedeon, L., Dascomb, S., Cooper, M., Murphy, M., Blakelock, K., Doolan, A. 2003; 349 (24): 2304-2315

    Abstract

    It is unclear whether therapy for human immunodeficiency virus type 1 (HIV-1) should be initiated with a four-drug or two sequential three-drug regimens.In this multicenter trial we compared initial therapy involving four-drug regimens containing efavirenz and nelfinavir in combination with either didanosine and stavudine or zidovudine and lamivudine with therapy involving two consecutive three-drug regimens the first of which contained either efavirenz or nelfinavir.A total of 980 subjects were followed for a median of 2.3 years. There was no significant difference in the occurrence of regimen failures between the group that received the four-drug regimen containing didanosine, stavudine, nelfinavir, and efavirenz and the groups that received the three-drug regimens beginning with didanosine, stavudine, and nelfinavir (hazard ratio for regimen failure, 1.24) or didanosine, stavudine, and efavirenz (hazard ratio, 1.01). There was no significant difference between the group that received the four-drug regimen containing zidovudine, lamivudine, nelfinavir, and efavirenz and the groups that received the three-drug regimens beginning with zidovudine, lamivudine, and nelfinavir (hazard ratio, 1.06) or zidovudine, lamivudine, and efavirenz (hazard ratio, 1.45). A four-drug regimen was associated with a longer time to the first regimen failure than the three-drug regimens containing didanosine, stavudine, and nelfinavir (hazard ratio for a first regimen failure, 0.55); didanosine, stavudine, and efavirenz (hazard ratio, 0.63); or zidovudine, lamivudine, and nelfinavir (hazard ratio, 0.49), but not the three-drug regimen containing zidovudine, lamivudine, and efavirenz (hazard ratio, 1.21).There was no significant difference in the duration of successful HIV-1 treatment between a single four-drug regimen and two consecutive three-drug regimens. Among these treatment strategies, initiating therapy with the three-drug regimen of zidovudine, lamivudine, and efavirenz is the optimal choice.

    View details for Web of Science ID 000187125000006

    View details for PubMedID 14668456

  • Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection NEW ENGLAND JOURNAL OF MEDICINE Robbins, G. K., De Gruttola, V., Shafer, R. W., Smeaton, L. M., Snyder, S. W., Pettinelli, C., Dube, M. P., Fischl, M. A., Pollard, R. B., Delapenha, R., Gedeon, L., van der Horst, C., Murphy, R. L., Becker, M. I., D'Aquila, R. T., Vella, S., Merigan, T. C., Hirsch, M. S., Nokta, M., Johnson, V., Morse, G., Putnam, B., Klebert, M., Martinez, A., Chiesi, A., Tomino, C., Deeks, S., Testa, M., Nevin, T., Levin, J., French, V., Fennell, O., Stevens, M., Grosso, R., Dusak, B., Hodder, S., Squibb, M., Brothers, C., Tolson, J., Leavitt, R., Manion, D., Ruiz, N., Morrisey, K., Quart, B., Jennings, C., Dascomb, S., Cooper, M., Murphy, M., Blakelock, K., Doolan, A. 2003; 349 (24): 2293-2303

    Abstract

    The optimal sequencing of antiretroviral regimens for the treatment of infection with human immunodeficiency virus type 1 (HIV-1) is unknown. We compared several different antiretroviral treatment strategies.This multicenter, randomized, partially double-blind trial used a factorial design to compare pairs of sequential three-drug regimens, starting with a regimen including zidovudine and lamivudine or a regimen including didanosine and stavudine in combination with either nelfinavir or efavirenz. The primary end point was the length of time to the failure of the second three-drug regimen.A total of 620 subjects who had not previously received antiretroviral therapy were followed for a median of 2.3 years. Starting with a three-drug regimen containing efavirenz combined with zidovudine and lamivudine (but not efavirenz combined with didanosine and stavudine) appeared to delay the failure of the second regimen, as compared with starting with a regimen containing nelfinavir (hazard ratio for failure of the second regimen, 0.71; 95 percent confidence interval, 0.48 to 1.06), as well as to delay the second virologic failure (hazard ratio, 0.56; 95 percent confidence interval, 0.29 to 1.09), and significantly delayed the failure of the first regimen (hazard ratio, 0.39) and the first virologic failure (hazard ratio, 0.34). Starting with zidovudine and lamivudine combined with efavirenz (but not zidovudine and lamivudine combined with nelfinavir) appeared to delay the failure of the second regimen, as compared with starting with didanosine and stavudine (hazard ratio, 0.68), and significantly delayed both the first and the second virologic failures (hazard ratio for the first virologic failure, 0.39; hazard ratio for the second virologic failure, 0.47), as well as the failure of the first regimen (hazard ratio, 0.35). The initial use of zidovudine, lamivudine, and efavirenz resulted in a shorter time to viral suppression.The efficacy of antiretroviral drugs depends on how they are combined. The combination of zidovudine, lamivudine, and efavirenz is superior to the other antiretroviral regimens used as initial therapy in this study.

    View details for Web of Science ID 000187125000005

    View details for PubMedID 14668455

  • Correlation of single photon emission computed tomography parameters as a noninvasive alternative to liver biopsies in assessing liver involvement in the setting of HIV and hepatitis C virus coinfection: A multicenter trial of the adult AIDS clinical trials group JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Shiramizu, B., Theodore, T., Bassett, R., Coel, M., Sherman, K. E., Glesby, I. J., Chow, D., Alston, B., Colquhoun, D., Merigan, T. C., Reichman, T. C., Berggren, R., Burning, W. J., Brobst, S. 2003; 33 (3): 329-335

    Abstract

    Performing a liver biopsy in patients infected with HIV and hepatitis C virus (HCV) is considered the standard of practice to assess hepatic involvement but carries risks to patients. This pilot study was designed to identify single photon emission computed tomography (SPECT) parameters that correlate with liver disease stage. HIV-coinfected and HCV-coinfected individuals undergoing a liver biopsy had a SPECT scan performed. The results showed that a number of SPECT parameters were associated with histologic changes in architecture, fibrosis, and cirrhosis, of which two SPECT parameters, the minimum pixel count for spleen region of interest and maximum pixel count for right hepatic lobe, correctly classified 39 of 46 SPECT/biopsy pairs. In conclusion, this pilot trial identified SPECT parameters that correlated with liver histology changes. A larger study is needed to demonstrate whether SPECT parameters alone or with other markers can provide information on fibrosis with the clinical significance obtained through liver biopsy.

    View details for Web of Science ID 000184077200006

    View details for PubMedID 12843743

  • HIV-1 protease variants from 100-fold drug resistant clinical isolates: expression, purification, and crystallization PROTEIN EXPRESSION AND PURIFICATION Vickrey, J. F., Logsdon, B. C., Proteasa, G., Palmer, S., Winters, M. A., Merigan, T. C., Kovari, L. C. 2003; 28 (1): 165-172

    Abstract

    High-resolution X-ray crystallographic structures of HIV-1 protease clinical variants complexed with licensed inhibitors are essential to understanding the fundamental cause of protease drug resistance. There is a need for structures of naturally evolved HIV-1 proteases from patients failing antiretroviral therapy. Here, we report the expression, purification, and crystallization of clinical isolates of HIV-1 protease that have been characterized to be more than 100 times less susceptible to US FDA approved protease inhibitors.

    View details for DOI 10.1016/S1046-5928(02)00650-2

    View details for Web of Science ID 000182063100022

    View details for PubMedID 12651121

  • Genotypic and phenotypic analysis of a novel 15-base insertion occurring between codons 69 and 70 of HIV type 1 reverse transcriptase AIDS RESEARCH AND HUMAN RETROVIRUSES Lobato, R. L., Kim, E. Y., Kagan, R. M., Merigan, T. C. 2002; 18 (10): 733-736

    Abstract

    An HIV-1 isolate possessing a 15-base insertion between codons 69 and 70 of the reverse transcriptase (RT) gene was derived from a patient plasma sample. Investigation of the insertion sequence revealed that this mutation is an ectopic duplication of the first 15 bases of the HIV-1 envelope gene. Phenotypic analysis yielded the following increases in resistance: 371-fold to zidovudine, 84-fold to lamivudine, 32-fold to abacavir, 15-fold to stavudine, 12-fold to didanosine, and 4-fold to zalcitabine. Phenotypic studies suggested that this change does not detract from the overall fitness of the virus. Together, data from this investigation support two conclusions. First, a previously unreported mechanism exists for generating diversity in HIV-1, namely long-distance duplication of genetic material from one portion of the genome to another. Second, large insertions in this region of RT are well tolerated and can confer high levels of resistance to multiple nucleoside analogue reverse transcriptase inhibitors.

    View details for Web of Science ID 000176673100009

    View details for PubMedID 12167282

  • A rapid phenotypic assay for detecting multiple nucleoside analogue reverse transcriptase inhibitor-resistant HIV-1 in plasma ANTIVIRAL THERAPY Qari, S. H., Winters, M., Vandamme, A. M., Merigan, T., Heneine, W. 2002; 7 (2): 131-139

    Abstract

    Zidovudine and other nucleoside analogue reverse transcriptase inhibitors (NRTIs), like zalcitabine and didanosine used for treatment of individuals infected with HIV-1, can select for viruses with Q151M and other associated mutations (for example, A62V, S68G, V751, F77L, F116Y) in the reverse transcriptase (RT) enzyme. These mutations confer resistance to multiple nucleoside analogues, and thereby compromise the efficacy of this class of drugs. Presently available phenotypic assays for detection of multiple nucleoside analogue resistant (MNR) HIV-1 require testing for each NRTI individually. Here we report an enzymatic RT assay that uses resistance to zidovudine triphosphate (zidovudine-TP) as a diagnostic biochemical marker of MNR HIV-1. This assay exploits the different biochemical mechanisms for zidovudine-resistance conferred by either Q151 M or T215Y/F mutations and the inability of conventional RT assays to detect T215Y/F-associated zidovudine resistance. The assay detects RT activity directly in plasma by using Amp-RT, an ultra-sensitive PCR-based RT assay. We show that enzymatic resistance to zidovudine-TP is specific to MNR RT and is distinguishable from both wild-type (WT) and RT containing classical zidovudine-resistant mutations (D67N, K70R, T215Y/F, K219Q). Compared to WT, MNR HIV-1 RT had 5- to 36-fold increases in the concentration of drug required to inhibit 50% (IC50) of RT activity, depending on the presence of Q151 M alone or with additional MNR mutations. A screening assay utilizing 1 microM zidovudine-TP was developed and validated on 14 reference isolates, 37 plasma specimens, and seven patient-derived viruses. Twenty-three specimens were found to have reduced susceptibility to zidovudine-TP, and all had Q151 M. In contrast, 21 specimens were sensitive to zidovudine-TP, of which 12 had WT genotypes, four had T215Y/F, and five had T69S-insertions along with T215Y/F mutations. This RT-based phenotypic assay provides a specific and rapid tool for the direct identification and monitoring of Q151M-associated MNR HIV-1 in plasma.

    View details for Web of Science ID 000177313500007

    View details for PubMedID 12212925

  • Both baseline HIV-1 drug resistance and antiretroviral drug levels are associated with short-term virologic responses to salvage therapy AIDS Baxter, J. D., Merigan, T. C., Wentworth, D. N., Neaton, J. D., Hoover, M. L., Hoetelmans, R. M., Piscitelli, S. C., Verbiest, W. H., MAYERS, D. L. 2002; 16 (8): 1131-1138

    Abstract

    To determine the impact of HIV-1 drug resistance at baseline and antiretroviral drug levels (DL) during follow-up on virologic response to the next antiretroviral regimen.Baseline genotypic and phenotypic susceptibility was obtained for plasma virus from patients failing a protease inhibitor-containing regimen. Untimed plasma antiretroviral DL were performed and the distribution of DL after 12 weeks of follow-up was classified as above (DLHigh) or below (DLLow) the median. Inhibitory quotients [IQ = (DL at week 12)/(fold change in IC50 to wild-type)] were determined for each drug in the regimen. Primary outcome was change in log10 plasma HIV-1 RNA viral load (DeltaVL) from baseline to 12 weeks.There were 137 patients who had baseline resistance data available for the antiretroviral drugs used in the salvage regimen, and DL at week 12. Each drug with DLHigh was associated with DeltaVL = -0.40 (P = 0.0002) while each drug with DLLow had DeltaVL = -0.16 (P = 0.11). In multivariate models DeltaVL associated with each active drug (defined by genotype) with DLHigh was -0.48 log10 (P < 0.0001), and with each active drug with DLLow was -0.22 (P = 0.03). The DeltaVL was -0.18 if no drugs in the regimen had an IQ > median, compared to -0.58 for one drug, -1.06 for two drugs, -0.86 for three drugs, and -1.44 for four or five drugs with IQ > median (P < 0.0001 for trend).In salvage therapy, both the number of active drugs and the DL for each drug in the new regimen determine the antiviral response.

    View details for Web of Science ID 000175760600006

    View details for PubMedID 12004271

  • Functional correlates of insertion mutations in the protease gene of human immunodeficiency virus type 1 isolates from patients JOURNAL OF VIROLOGY Kim, E. Y., Winters, M. A., Kagan, R. M., Merigan, T. C. 2001; 75 (22): 11227-11233

    Abstract

    Twenty-four of over 24,000 patients genotyped over the past 3 years were found to have human immunodeficiency virus (HIV) isolates that possess an insert in the protease gene. In this report, we evaluated the spectrum of protease gene insertion mutations in patient isolates and analyzed the effect of these various insertion mutations on viral phenotypes. The inserts were composed of 1, 2, 5, or 6 amino acids that mapped at or between codons 35 and 38, 17 and 18, 21 and 25, or 95 and 96. Reduced susceptibility to protease inhibitors was found in isolates which possess previously reported drug resistance mutations. Fitness assays, including replication and competition experiments, showed that most of the isolates with inserts grew somewhat better than their counterparts with a deletion of the insert. These experiments demonstrate that, rarely, insertion mutations can develop in the HIV type 1 protease gene, are no more resistant than any other sequences which have similar associated resistance mutations, and can provide a borderline advantage in replication.

    View details for Web of Science ID 000171652700066

    View details for PubMedID 11602763

  • Effect of therapeutic immunization with HIV type 1 recombinant glycoprotein 160 ImmunoAG vaccine in HIV-infected individuals with CD4(+) T cell counts of <= 500 and 200-400/mm(3) (AIDS Clinical Trials Group study 246/946) AIDS RESEARCH AND HUMAN RETROVIRUSES Kundu-Raychaudhuri, S., SEVIN, A., Kilgo, P., Nokta, M., Pollard, R. B., Merigan, T. C. 2001; 17 (15): 1371-1378

    Abstract

    AIDS Clinical Trials Group (ACTG) 246/946 was a double-blinded, randomized, controlled trial of HIV-1 MN rgp160 ImmunoAG vaccine in HIV-infected patients with CD4(+) T cell counts >or=500 and 200-400/mm(3). The main objectives were to study the safety and immunogenicity of this vaccine and to study the persistence of the immune responses after vaccination over a longer period of time. Fifteen patients with CD4(+) T cell counts of >or=500/mm(3) were enrolled in the ACTG 246 study. ACTG 246 patients received a monthly injection of vaccine or control for 6 months and then injections every 2 months. After completion of this study, seven new patients with CD4(+) T cell counts of 200-400/mm(3) entered into the ACTG 946 study. These study patients received highly active antiretroviral therapy (HAART) (ritonavir, didanosine, and stavudine) for 9 weeks to stabilize their viral load and then each patient received a monthly injection of vaccine or control substance for 6 months with HAART. The study of these two relatively small populations showed that the vaccine was safe without any adverse effect both in the patients with CD4(+) T cell counts of >or=500 and 200-400/mm(3). The vaccine was also immunogenic in patients with CD4(+) T cell counts of >or=500/mm(3) as measured by gp160-specific lymphocyte proliferative responses, and it persisted after they had received more than six vaccine injections, for a longer period of time.

    View details for Web of Science ID 000171857000001

    View details for PubMedID 11679149

  • Variants other than aspartic acid at codon 69 of the human immunodeficiency virus type 1 reverse transcriptase gene affect susceptibility to nucleoside analogs ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Winters, M. A., Merigan, T. C. 2001; 45 (8): 2276-2279

    Abstract

    The T69D mutation in the human immunodeficiency virus type 1 reverse transcriptase (RT) gene has been associated with reduced susceptibility to dideoxycytosine (ddC); however, several other mutations at codon 69 have been observed in antiretroviral drug-treated patients. The Stanford HIV RT and Protease Sequence Database was interrogated and showed that 23% of patients treated with nucleoside RT inhibitors (NRTI) had mutations at codon 69. These variants included T69N, -S, -A, -G, -E, -I, and -K mutations that were present in patients treated with NRTI but not in drug-naive patients. Treatment history information showed that a substantial percentage of these codon 69 changes occurred in patients administered non-ddC-containing regimens. Different and specific patterns of other RT gene mutations were associated with the various codon 69 mutations. Drug susceptibility assays showed that viral constructs containing codon 69 variants could have reduced susceptibility to ddC and other RT inhibitors. These results suggest that the T69D mutation is not the only codon 69 variant associated with drug resistance and that ddC is not the only drug affected.

    View details for Web of Science ID 000169999700013

    View details for PubMedID 11451685

  • Anti-HIV type 1 activity of 3 '-fluoro-3 '-deoxythymidine for several different multidrug-resistant mutants AIDS RESEARCH AND HUMAN RETROVIRUSES Kim, E. Y., Vrang, L., Oberg, B., Merigan, T. C. 2001; 17 (5): 401-407

    Abstract

    The objective of this work was to test the antiviral activity of a potent nucleoside reverse transcriptase inhibitor, 3'-fluoro-3'-deoxythymidine (FLT), on both a wild-type human immunodeficiency virus (HIV-1) isolate and multidrug-resistant HIV-1 patient isolates. Drug-resistant viral isolates were selected on the basis of four different categories of well-characterized and representative multidrug-resistant mutants. The isolates included three variants containing 151M alone or in combination; three variants containing 215Y and 41L, 67N, 184V, 210W, and 219N in combination; two insertion mutant viruses (69 + EA and 69 + SA); and two deletion mutant viruses (del67NG and del67GS), the latter two groups both also containing other significant mutations. The activity of FLT and AZT against these isolates was determined by drug susceptibility assays and by measuring viral antigen p24 by ELISA. The cytotoxicity of FLT and AZT was assessed in PHA-stimulated PBMCs. Development of resistant mutants under FLT pressure was attempted by passaging HIV-1 isolates in SupT1 cells and stepwise increasing the concentration of FLT. The multidrug-resistant mutant HIV-1 isolates exhibited 7-fold to >100-fold increased resistance to AZT, but showed IC(50) values for FLT of 0.0014-0.0168 microM, which were lower than or similar to that of wild type (0.0075 microM). The cellular cytotoxicities of FLT and AZT fell into a similar range in PBMCs. The development of HIV mutants resistant to FLT appeared to be slower than for other RT inhibitors. HIV isolates with mutations resulting in multidrug resistance had no evidence of resistance to FLT. FLT may be useful in salvage therapies for patients harboring resistant strains and a reassessment of its therapeutic potential seems required.

    View details for Web of Science ID 000167680800003

    View details for PubMedID 11282008

  • Genotypic, phenotypic, and modeling studies of a deletion in the beta 3-beta 4 region of the human immunodeficiency virus type 1 reverse transcriptase gene that is associated with resistance to nucleoside reverse transcriptase inhibitors JOURNAL OF VIROLOGY Winters, M. A., Coolley, K. L., Cheng, P., Girard, Y. A., Hamdan, H., Kovari, L. C., Merigan, T. C. 2000; 74 (22): 10707-10713

    Abstract

    Point mutations and inserts in the beta3-beta4 region of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) are associated with resistance to nucleoside analog inhibitors. This report describes HIV-1 strains from seven patients that were found to have a 3-bp deletion in the beta3-beta4 region of the RT gene. These patient strains also had a mean of 6.2 drug resistance-associated mutations in their RT genes (range, 3 to 10 mutations). The deletion was most frequently found in strains with the Q151M mutation. Nonnucleoside RT inhibitor mutations were found in six of seven strains. Culture-based drug sensitivity assays showed that deletion-containing isolates had reduced susceptibility to four to eight RT inhibitors. Site-directed mutagenesis experiments showed that the deletion alone conferred reduced susceptibility to nucleoside analogs. Changes in the three-dimensional models of the RT deletion mutants were consistently observed at the beta3-beta4 loop and at helices C and E in both the presence and the absence of dTTP. Loss of hydrogen bonds between the RT and dTTP were also observed in the RT deletion mutant. These results suggest that the deletion in the RT gene contributes to resistance to several nucleoside analogs through a complex interaction with other mutations in the RT gene.

    View details for Web of Science ID 000090083800046

    View details for PubMedID 11044115

  • Highly active antiretroviral therapy results in HIV type 1 suppression in lymph nodes, increased pools of naive T cells, decreased pools of activated T cells, and diminished frequencies of peripheral activated HIV type 1-specific CD8(+) T cells AIDS RESEARCH AND HUMAN RETROVIRUSES Gray, C. M., Lawrence, J., Ranheim, E. A., Vierra, M., Zupancic, M., Winters, M., Altman, J., Montoya, J., Zolopa, A., Schapiro, J., Haase, A. T., Merigan, T. C. 2000; 16 (14): 1357-1369

    Abstract

    This study examines sequential lymph nodes from 13 drug-naive patients before and after 24 weeks of highly active antiretroviral therapy (HAART). A multipronged approach was used to study changes in HIV-1 RNA in each paired lymph node in relation to tissue architecture and frequency of naive T cells. After 24 weeks, all patients showed significant suppression of plasma viral load and 12 of 13 showed concordant viral suppression in the lymph node (p = 0.001). Using in situ hybridization and quantitative image analysis, we showed that HIV-1 RNA was reduced to below detectable levels (two copies per cell) in follicular dendritic cell (FDC) and mononuclear cell pools. Independent immunohistochemical analysis of lymph node sections revealed that 5 of 13 patients displayed increased FDC networks and 6 of 13 showed no change and all patients showed increases in tissue-resident CD4+ cells. All lymph node biopsies at 24 weeks showed increased proportions of CD4+ and CD8+ cells coexpressing the naive markers CD45RA and CD62L when compared with baseline values. Significant correlations existed between viral load suppression and loss of activated CD8+ T cells after 24 weeks in both lymph node and blood, which was mirrored by significantly lowered frequencies of activated peripheral Gag peptide/MHC tetramer+ CD8+ cells. Overall, these data show that a potent and successful treatment strategy that significantly suppresses and removes FDC-resident HIV-1 results in improvements in lymphoid architecture and by so doing provides the structures available for increased numbers of naive cells to interact with cognate antigen. In addition, our article shows that suppression of HIV-1 replication results in diminished frequencies of peripherally activated antigen-specific CD8+ cells.

    View details for Web of Science ID 000089593100004

    View details for PubMedID 11018855

  • A randomized study of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy AIDS Baxter, J. D., MAYERS, D. L., Wentworth, D. N., Neaton, J. D., Hoover, M. L., Winters, M. A., Mannheimer, S. B., Thompson, M. A., Abrams, D. I., Brizz, B. J., Ioannidis, J. P., Merigan, T. C. 2000; 14 (9): F83-F93

    Abstract

    To determine the short-term effects of using genotypic antiretroviral resistance testing (GART) with expert advice in the management of patients failing on a protease inhibitor and two nucleoside reverse transcriptase inhibitors.Prospective randomized controlled trial.Multicenter community-based clinical trials network.One-hundred and fifty-three HIV-infected adults with a threefold or greater rise in plasma HIV-1 RNA on at least 16 weeks of combination antiretroviral therapy.Randomization was either to a GART group, where genotype interpretation and suggested regimens were provided to clinicians, or to a no-GART group, where treatment choices were made without such input.Plasma HIV-1 RNA levels and CD4 cell counts were measured at 4, 8, and 12 weeks following randomization. The primary endpoint was change in HIV-1 RNA levels from baseline to the average of the 4 and 8 week levels.The average baseline CD4 cell count was 230 x 10(6) cells/l and the median HIV-1 RNA was 28,085 copies/ml. At entry, 82 patients were failing on regimens containing indinavir, 51 on nelfinavir, 11 on ritonavir, and nine on saquinavir. HIV-1 RNA, averaged at 4 and 8 weeks, decreased by 1.19 log10 for the 78 GART patients and -0.61 log10 for the 75 no-GART patients (treatment difference: -0.53 log, 95% confidence interval, -0.77 to -0.29; P = 0.00001). Overall, the best virologic responses occurred in patients who received three or more drugs to which their HIV-1 appeared to be susceptible.In patients failing triple drug therapy, GART with expert advice was superior to no-GART as measured by short-term viral load responses.

    View details for Web of Science ID 000087735700001

    View details for PubMedID 10894268

  • In vivo persistence of donor cells following adoptive transfer of allogeneic dendritic cells in HIV-infected patients CELL TRANSPLANTATION Shapero, M. H., Kundu, S. K., Engleman, E., Laus, R., van Schooten, W. C., Merigan, T. C. 2000; 9 (3): 307-317

    Abstract

    Peripheral blood samples from HIV-seropositive individuals enrolled in a pilot clinical trial investigating the use of allogeneic dendritic cell therapy were evaluated for mixed chimerism. In this study, dendritic cells from HLA-identical, HIV-seronegative siblings were used. Patients received an infusion of dendritic cells pulsed with HIV MN gp160 protein or with peptides from HLA-A2 restricted epitopes of env, gag, and pol proteins every month for 6-9 months. Of the five allogeneic dendritic cell recipients, two showed increases in HIV antigen-specific immune responses. Allele-specific polymorphisms were identified in three sib-pairs that allowed infused donor cells to be detected using sensitive PCR-based molecular methods. Analysis of blood samples from patients showed similar patterns of donor cell persistence after the first infusion, in that cells were detectable for at least 1 week. Also, differences were observed in the kinetics of cell survival between the first and subsequent infusion cycles in all three patients. This suggests variation in HIV-specific immune responses detected among these three patients was not due to differences in persistence of infused donor cells.

    View details for Web of Science ID 000088921000002

    View details for PubMedID 10972330

  • Frequency of antiretroviral drug resistance mutations in HIV-1 strains from patients failing triple drug regimens ANTIVIRAL THERAPY Winters, M. A., Baxter, J. D., MAYERS, D. L., Wentworth, D. N., Hoover, M. L., Neaton, J. D., Merigan, T. C. 2000; 5 (1): 57-63

    Abstract

    The frequency of protease and reverse transcriptase (RT) gene mutations was determined in HIV-1 strains from 153 patients entering the CPCRA 046 (GART) study who were failing triple-drug regimens consisting of one protease inhibitor (PI) and two RT inhibitors. Population-based sequence analyses showed that nearly all patients had similar RT gene mutations regardless of prior drug exposure, although the M184V mutation was significantly less prevalent in patients not recently treated with lamivudine. Whilst typical inhibitor-specific ('signature') protease gene mutations were found in patients failing their first PI, these mutations were significantly less likely to be found in patients exposed to two or more PIs. Protease gene mutations associated with multi-PI resistance were more likely to be observed in patients treated with more than one PI. These results suggest sequential treatment with PIs select for a relatively limited number of protease gene mutations that likely originated during early PI therapy. These protease gene mutations and a similarly limited set of RT gene mutations appear to be responsible for treatment failure in antiretroviral therapy.

    View details for Web of Science ID 000087183000011

    View details for PubMedID 10846594

  • HIV-1 genotypic resistance patterns predict response to saquinavir-ritonavir therapy in patients in whom previous protease inhibitor therapy had failed ANNALS OF INTERNAL MEDICINE Zolopa, A. R., Shafer, R. W., Warford, A., Montoya, J. G., Hsu, P., KATZENSTEIN, D., Merigan, T. C., Efron, B. 1999; 131 (11): 813-?

    Abstract

    Tests for resistance to HIV drugs are available for clinical use; however, their predictive value has not been fully assessed.To determine HIV-1 genotypic predictors of a virologic response to saquinavir-ritonavir therapy in patients in whom at least one previous protease inhibitor-containing regimen had failed and to compare the predictive value of baseline genotype with that of standard clinical evaluation.Retrospective clinical cohort study.University-based HIV clinic.54 HIV-1-infected adults treated with saquinavir-ritonavir who had experienced virologic failure while receiving a protease inhibitor-containing regimen for at least 3 months.HIV-1 reverse transcriptase and protease gene sequences, CD4 cell counts, clinical characteristics, detailed antiretroviral treatment history, and plasma HIV-1 RNA levels at baseline and at three follow-up time points (median, 4, 12, and 26 weeks). Virologic failure was defined as a plasma HIV RNA level greater than 1000 copies/mL.In 22 patients (41%), a plasma HIV-1 RNA level less than 500 copies/mL was achieved by week 12; in 15 patients (28%), this response was maintained through week 26. Clinical characteristics predicting a poorer response included a diagnosis of AIDS, lower CD4 cell count, and higher plasma HIV RNA level (P<0.03). Number of previous nucleoside reverse transcriptase inhibitors, previous protease inhibitor therapy, and duration of previous protease inhibitor therapy were predictors of poorer response (P<0.01). Multivariate regression models revealed that protease mutations present at the initiation of saquinavir-ritonavir therapy were the strongest predictors of virologic response. A model of clinical features explained up to 45% of the variation in virologic outcomes by week 12, whereas the explained variance was 71% when genotypic predictors were included.In patients in whom protease inhibitor-containing antiretroviral therapy fails, HIV-1 genotype is predictive of virologic response to subsequent therapy. This predictive capacity adds to that of standard clinical evaluation.

    View details for Web of Science ID 000084053200002

    View details for PubMedID 10610625

  • Delayed-type hypersensitivity to recombinant HIV envelope glycoprotein (rgp160) after immunization with homologous antigen JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Katzenstein, D. A., Kundu, S., Spritzler, J., SMOLLER, B. R., Haszlett, P., Valentine, F., Merigan, T. C. 1999; 22 (4): 341-347

    Abstract

    Delayed-type hypersensitivity (DTH) responses to intradermal recombinant HIV envelope glycoprotein (rgp160) may assess cell-mediated immune responses to HIV envelope. In three studies, DTH and lymphocyte proliferation responses to rgp160 were obtained in a total of 106 HIV-seropositive subjects with CD4+ counts >400 cells/mm3. Several subjects participated in more than one study. Before immunization, DTH responses were seen in 5 of 56 (9%) of HIV-infected study subjects. After immunization with an alum-adjuvanted experimental rgp160 vaccine, DTH responses were seen in 46 of 52 (89%). Using in vitro lymphocyte proliferation activity (LPA) to rgp160 as an indication of cellular immune response, skin testing has a sensitivity of 0.75 (95% confidence Interval [CI], 0.59-0.88) and a specificity of 0.84 (95% CI, 0.72-0.92). Biopsy samples of skin that had tested positive confirmed the presence of a DTH reaction with a predominance of CD4+ T cells in the perivascular, inflammatory infiltrate. Skin testing before and after immunization with candidate AIDS vaccines could provide a simple method in the field to assess new cell mediated immune responses.

    View details for Web of Science ID 000085336400004

    View details for PubMedID 10634195

  • Hydroxyurea enhances the activities of didanosine, 9-[2(phosphonylmethoxy)ethyl] adenine, and 9-[2(phosphonylmethoxy)propyl]adenine against drug-susceptible and drug-resistant human immunodeficiency virus isolates ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Palmer, S., Shafer, R. W., Merigan, T. C. 1999; 43 (8): 2046-2050

    Abstract

    We assessed the effects of hydroxyurea (HU) at a concentration of 50 microM on the in vitro activities of 2',3'-dideoxyinosine (ddI), 9-[2-(phosphonylmethoxy)ethyl]adenine (PMEA), and 9-[2-(phosphonylmethoxy)propyl]adenine (PMPA) against a wild-type human immunodeficiency virus (HIV) type 1 (HIV-1) laboratory isolate and a panel of five well-characterized drug-resistant HIV isolates. Fifty micromolar HU significantly increased the activities of ddI, PMEA, and PMPA against both the wild-type and the drug-resistant HIV-1 isolates. In fixed combinations, both ddI and PMEA were synergistic with HU against wild-type and drug-resistant viruses.

    View details for Web of Science ID 000081789200037

    View details for PubMedID 10428934

  • Impact of prophylactic immediate posttransplant ganciclovir on development of transplant atherosclerosis - A post hoc analysis of a randomized, placebo-controlled study CIRCULATION Valantine, H. A., Gao, S. Z., Menon, S. G., Renlund, D. G., Hunt, S. A., Oyer, P., Stinson, E. B., Brown, B. W., Merigan, T. C., Schroeder, J. S. 1999; 100 (1): 61-66

    Abstract

    Coronary artery disease occurs in an accelerated fashion in the donor heart after heart transplantation (TxCAD), but the cause is poorly understood. The risk of developing TxCAD is increased by cytomegalovirus (CMV) infection and decreased by use of calcium blockers. Our group observed that prophylactic administration of ganciclovir early after heart transplantation inhibited CMV illness, and we now propose to determine whether this therapy also prevents TxCAD.One hundred forty-nine consecutive patients (131 men and 18 women aged 48+/-13 years) were randomized to receive either ganciclovir or placebo during the initial 28 days after heart transplantation. Immunosuppression consisted of muromonab-CD3 (OKT-3) prophylaxis and maintenance with cyclosporine, prednisone, and azathioprine. Mean follow-up time was 4.7+/-1.3 years. In a post hoc analysis of this trial designed to assess efficacy of ganciclovir for prevention of CMV disease, we compared the actuarial incidence of TxCAD, defined by annual angiography as the presence of any stenosis. Because calcium blockers have been shown to prevent TxCAD, we analyzed the results by stratifying patients according to use of calcium blockers. TxCAD could not be evaluated in 28 patients because of early death or limited follow-up. Among the evaluable patients, actuarial incidence of TxCAD at follow-up (mean, 4.7 years) in ganciclovir-treated patients (n=62) compared with placebo (n=59) was 43+/-8% versus 60+/-10% (P<0.1). By Cox multivariate analysis, independent predictors of TxCAD were donor age >40 years (relative risk, 2.7; CI, 1.3 to 5.5; P<0.01) and no ganciclovir (relative risk, 2.1; CI, 1.1 to 5.3; P=0.04). Stratification on the basis of calcium blocker use revealed differences in TxCAD incidence when ganciclovir and placebo were compared: no calcium blockers (n=53), 32+/-11% (n=28) for ganciclovir versus 62+/-16% (n=25) for placebo (P<0.03); calcium blockers (n=68), 50+/-14% (n=33) for ganciclovir versus 45+/-12% (n=35) for placebo (P=NS).TxCAD incidence appears to be lower in patients treated with ganciclovir who are not treated with calcium blockers. Given the limitations imposed by post hoc analysis, a randomized clinical trial is required to address this issue.

    View details for Web of Science ID 000081279300013

    View details for PubMedID 10393682

  • Viral resistance testing: practical issues and future opportunities - interview with Thomas Merigan, M.D. Interview by John S. James. AIDS treatment news Merigan, T. 1999: 1-6

    View details for PubMedID 11366300

  • Antiviral activity of the human immunodeficiency virus type 1 specific nonnucleoside reverse transcriptase inhibitor HBY097 alone and in combination with zidovudine in a phase II study JOURNAL OF INFECTIOUS DISEASES Kleim, J. P., Winters, M., Dunkler, A., Suarez, J. R., Riess, G., Winkler, I., Balzarini, J., Oette, D., Merigan, T. C. 1999; 179 (3): 709-713

    Abstract

    The safety and antiviral activity of the second-generation nonnucleoside inhibitor HBY 097 was investigated in asymptomatic or mildly symptomatic human immunodeficiency virus (HIV)-1-infected patients in a randomized, double-blinded, dose-escalation study. Mean maximum virus load decreases ranged from -1.31 log10 copies/mL of plasma at week 1 in the group receiving HBY 097 monotherapy (250 mg three times daily) to -2.19 log10 copies/mL at week 4 in the group receiving zidovudine plus HBY 097 (750 mg three times daily). After 12 weeks, these patients had viral RNA copy numbers 1.05 log10 below baseline. Genotypic analysis of resistance development revealed reverse transcriptase K103N variants in most patients, which was associated with less durable efficacy of HBY 097 treatment. Fewer patients receiving combination therapy with high-dose HBY 097 developed the K103N variant (P<.01). HBY 097 caused pronounced acute suppression of HIV-1 replication both in combination with zidovudine and alone. Therefore, sustained antiviral activity can be expected from multiple combination therapy regimens including a quinoxaline derivative.

    View details for Web of Science ID 000079566700026

    View details for PubMedID 9952383

  • Clinical cross-resistance between the HIV-1 protease inhibitors saquinavir and indinavir and correlations with genotypic mutations AIDS Schapiro, J. M., Winters, M. A., Lawrence, J., Merigan, T. C. 1999; 13 (3): 359-365

    Abstract

    To determine the clinical efficacy of the HIV-1 protease inhibitor indinavir (IDV) in saquinavir (SQV)-experienced patients and delineate the developing drug-resistance patterns.Open-label prospective clinical trial.University hospital research center.Ten patients who had completed a SQV monotherapy study in which they had received SQV at a dose of 3600 or 7200 mg daily (two and fourfold the standard dose).At enrollment patients received IDV for 4 weeks as monotherapy, after which zidovudine (ZDV) and lamivudine (3TC) were added to their drug regimen. Patients then received combination therapy (IDV-ZDV-3TC) for an additional 20 weeks to complete a total of 24 weeks of therapy.Plasma HIV RNA viral load and CD4+ T-cell counts were monitored. Sequencing of the HIV protease gene was performed to determine the development of resistance mutations. Plasma samples for sequencing were taken before initial SQV therapy, after SQV therapy before starting IDV, and after 24 weeks of IDV therapy.The average duration of high-dose SQV before starting IDV was 58+/-29.2 weeks. A 0.58 log10 RNA copies/ml increase was noted during the 3-week washout phase followed by a mean reduction in plasma HIV RNA viral load of 1.2 log10 RNA copies/ml after 4 weeks of IDV. After the addition of ZDV and 3TC at week 4, HIV RNA continued to fall reaching a mean reduction of 1.96 log10 RNA copies/ml at week 24. Plasma HIV RNA was below 400 RNA copies/ml in six out of nine patients at week 24. CD4+ T-cell counts showed a gradual rise from 328 x 10(6)/l to 453 x 10(6)/l by week 24. SQV therapy had resulted in multiple mutations in the protease gene. Six of the patients had developed five or more mutations: L90M in two, G48V in four (of which three also contained L101), and V82A in three. Patients in whom plasma HIV RNA was not durably suppressed by subsequent IDV combination therapy developed multiple (up to four) additional mutations within 24 weeks, including codons 54, 82 and 93 amongst others. No clear correlation was found between the mutations that had developed in individual patients after SQV and the subsequent efficacy of IDV.Prolonged use of SQV at potent doses in the presence of elevated viral load levels resulted in the development of multiple resistance mutations. Individual resistance patterns varied greatly between patients, as did their virological response to therapy. Resistance assays may be useful in identifying which patients will benefit from salvage therapy with a second protease inhibitor.

    View details for Web of Science ID 000079196000008

    View details for PubMedID 10199226

  • Frequency of class I HLA-restricted anti-HIV CD8(+) T cells in individuals receiving highly active antiretroviral therapy (HAART) JOURNAL OF IMMUNOLOGY Gray, C. M., Lawrence, J., Schapiro, J. M., Altman, J. D., Winters, M. A., Crompton, M., Loi, M., Kundu, S. K., DAVIS, M. M., Merigan, T. C. 1999; 162 (3): 1780-1788

    Abstract

    Peptide/MHC tetrameric complexes were used to enumerate the frequency of HLA class I-restricted epitope-specific CD8+ T cells in 18 HLA-A*0201 HIV type 1-infected asymptomatic patients. HLA-A*0201 molecules were complexed to HIV Gag p17 (amino acids 77-85) and reverse transcriptase (amino acids 464-472) peptides, biotinylated, and bound to streptavidin-phycoerythrin to form tetramers. We show in this study that 17 of 18 HIV-1-infected asymptomatic patients have circulating frequencies of 1/50-1/1000 CD8+ T cells that recognize both Gag and Pol CTL epitopes or either epitope alone. The functional nature of these cells is open to interpretation, as we show that despite relatively high frequencies of fresh epitope-specific CD8+ T cells, variant epitope sequences in viral plasma progeny were rare. In addition, the majority of tetramer-positive cells did not display discernible fresh CTL activity; only after restimulation with specific peptide in culture was there an expansion of epitope-specific CD8+ cells, correlating with high CTL activity. These data suggest that fresh tetramer-stained cells probably represent memory precursors; we demonstrate, with the application of highly active antiretroviral therapy, that the interruption of chronic antigenic stimulation causes significant reductions in the frequency of these cells in five of six patients. In conclusion, this study provides evidence that persistently replicating viral populations are probably required to maintain high frequencies of HIV-1 epitope-specific CD8+ T cells in asymptomatic chronically infected individuals

    View details for Web of Science ID 000078261000071

    View details for PubMedID 9973442

  • Resistance mutations to zidovudine and saquinavir in patients receiving zidovudine plus saquinavir or zidovudine and zalcitabine plus saquinavir in AIDS Clinical Trials Group 229 JOURNAL OF INFECTIOUS DISEASES Schapiro, J. M., Lawrence, J., Speck, R., Winters, M. A., Efron, B., COOMBS, R. W., Collier, A. C., Merigan, T. C. 1999; 179 (1): 249-253

    Abstract

    The relationships among treatment regimens, plasma human immunodeficiency virus (HIV) RNA levels, and resistance mutations to saquinavir (codons 48 and 90) and zidovudine (codon 215) were examined in a cohort of 144 patients from the AIDS Clinical Trials Group 229 study. After 24-40 weeks of therapy, no patients who had received the two-drug combination (zidovudine plus saquinavir) had only codon 48 mutations, 45.8% had only codon 90 mutations, and 8.3% had both codon 48 and 90 mutations. Mutations developed by patients who had received the three-drug combination (zidovudine and zalcitabine plus saquinavir) were codon 48 alone in 1.4%, codon 90 alone in 33.3%, and both codons 48 and 90 in 4.2%. The difference between the groups showed a trend toward reduced mutations with three versus two drugs but did not reach significance (P=.11, two-sided chi2). Higher baseline HIV RNA levels correlated with the development of protease mutations. Mutations at codon 215 were present in 82% of all patients at baseline and in 87% after therapy.

    View details for Web of Science ID 000077725000035

    View details for PubMedID 9841849

  • Role of preimmunization virus sequences in cellular immunity in HIV-infected patients during HIV type 1 MN recombinant gp160 immunization AIDS RESEARCH AND HUMAN RETROVIRUSES Kundu, S. K., Dupuis, M., Sette, A., CELIS, E., Dorner, F., Eibl, M., Merigan, T. C. 1998; 14 (18): 1669-1678

    Abstract

    The effect of patient preimmunization virus sequences on CTL responses during gp160 immunization were studied. Ten HLA-A2+, HIV+ asymptomatic patients with CD4+ T cells >500/mm3 were given two courses of HIV-1 MN rgp160 vaccine over a 2-year period. Envelope epitope-specific CTL responses, using PBMCs, were measured against peptide-coated autologous B lymphoblastoid cell lines. Optimum CTL epitopes were determined by HLA-A2-binding affinity of 9- to 10-mer peptides containing the HLA-A2.1-binding motif. Ten of the high- or intermediate-binding peptides were conserved among >50% of reported clade B HIV strains. These peptide-specific CTL activities and the patient virus sequences in peptide-coding regions were monitored. Six patients showed envelope peptide-specific CTL responses, which correlated with the presence of whole envelope antigen-specific CTL responses. Five of these patients, who showed responses to epitopes in the gp41 region (aa 814-824), had preimmunization virus similar to the vaccine sequence in this region. Three patients who did not show these epitope-specific responses had initially different sequences in the HIV gene encoding that region. The epitope-specific CTL responses appear to reflect recall responses, as only patients infected with virus containing the vaccine sequence developed them and they could be recalled with a second set of vaccine injections. This appears to be reminiscent of the concept of T cell "original antigenic sin." This vaccine was also immunogenic as measured by gp160-specific lymphocyte-proliferative responses. However, increased immune responses did not impact the HIV load or CTL epitope sequences during therapy.

    View details for Web of Science ID 000077520000009

    View details for PubMedID 9870321

  • A 6-basepair insert in the reverse transcriptase gene of human immunodeficiency virus type 1 confers resistance to multiple nucleoside inhibitors JOURNAL OF CLINICAL INVESTIGATION Winters, M. A., Coolley, K. L., Girard, Y. A., Levee, D. J., Hamdan, H., Shafer, R. W., Katzenstein, D. A., Merigan, T. C. 1998; 102 (10): 1769-1775

    Abstract

    While many point mutations in the HIV-1 reverse transcriptase (RT) confer resistance to antiretroviral drugs, inserts or deletions in this gene have not been previously characterized. In this report, 14 RT inhibitor-treated patients were found to have HIV-1 strains possessing a 6-basepair insert between codons 69 and 70 of the RT gene. Known drug resistance mutations were also observed in these strains, with T215Y appearing in all strains. Genotypic analysis indicated that the inserts had substantial nucleotide variability that resulted in relatively restricted sets of amino acid sequences. Linkage of patients' treatment histories with longitudinal sequencing data showed that insert strains appeared during drug regimens containing ddI or ddC, with prior or concurrent AZT treatment. Drug susceptibility tests of recombinant patient isolates showed reduced susceptibility to nearly all nucleoside RT inhibitors. Site- directed mutagenesis studies confirmed the role of the inserts alone in conferring reduced susceptibility to most RT inhibitors. The addition of AZT-associated drug resistance mutations further increased the range and magnitude of resistance. These results establish that inserts, like point mutations, are selected in vivo during antiretroviral therapy and provide resistance to multiple nucleoside analogs.

    View details for Web of Science ID 000077205900001

    View details for PubMedID 9819361

  • Human immunodeficiency virus type 1 protease genotypes and in vitro protease inhibitor susceptibilities of isolates from individuals who were switched to other protease inhibitors after long-term saquinavir treatment JOURNAL OF VIROLOGY Winters, M. A., Schapiro, J. M., Lawrence, J., Merigan, T. C. 1998; 72 (6): 5303-5306

    Abstract

    An understanding of the mechanisms of virologic cross-resistance between human immunodeficiency virus type 1 protease inhibitors is important for the establishment of effective treatment strategies for patients who no longer respond to their initial protease inhibitor. Protease gene sequencing results from patients treated with saquinavir showed significant increases in the frequency of the G48V protease mutation in patients receiving higher doses of the drug. In addition, all six patients who developed the G48V mutation during saquinavir therapy developed the V82A mutation either on continued saquinavir or after a switch to nelfinavir or indinavir. In vitro susceptibility assays showed that all 13 isolates with reduced susceptibilities to two or more protease inhibitors had either the G48V or L90M mutation, along with an average of six other protease mutations. Reduced susceptibility to nelfinavir was found in 14 isolates, but only 1 possessed the D30N mutation. These results suggest that mutations selected in vivo by initial saquinavir therapy may provide more cross-resistance to the other protease inhibitors than has been previously reported.

    View details for Web of Science ID 000073497600093

    View details for PubMedID 9573309

  • Multiple concurrent reverse transcriptase and protease mutations and multidrug resistance of HIV-1 isolates from heavily treated patients ANNALS OF INTERNAL MEDICINE Shafer, R. W., Winters, M. A., Palmer, S., Merigan, T. C. 1998; 128 (11): 906-911

    Abstract

    Drug resistance of HIV-1 is an obstacle to the long-term efficacy of antiretroviral therapy.To characterize reverse transcriptase and protease genes of multidrug-resistant HIV-1 isolates.Descriptive case series.Academic medical center.Four consecutive patients with HIV-1 infection were selected because they had previously received many antiretroviral drugs and had not achieved plasma HIV-1 RNA suppression despite treatment with several three-drug combinations.Reverse transcriptase sequencing, protease sequencing, and drug susceptibility testing of HIV-1.Isolates of HIV-1 from the four patients shared seven protease mutations and eight reverse transcriptase mutations. These mutations were present in biological clones and at three time points in three of the patients. Susceptibility testing showed high-level resistance (30-fold to >100-fold) to zidovudine, lamivudine, saquinavir, indinavir, and nelfinavir and lower-level resistance (3-fold to 5-fold) to didanosine, zalcitabine, and stavudine.Simultaneous resistance to almost all available antiretroviral drugs may occur in HIV-1. The concordance and persistence of mutations in drug-resistant HIV-1 isolates suggest that some combinations of reverse transcriptase and protease mutations give the virus a selective advantage in the presence of various drug combinations.

    View details for Web of Science ID 000073808600005

    View details for PubMedID 9634429

  • Changes in CD4(+) and CD8(+) T cell subsets in response to highly active antiretroviral therapy in HIV type 1-infected patients with prior protease inhibitor experience AIDS RESEARCH AND HUMAN RETROVIRUSES Gray, C. M., Schapiro, J. M., Winters, M. A., Merigan, T. C. 1998; 14 (7): 561-569

    Abstract

    This study explores whether previous failures on antiretroviral drug regimens preclude the possibility of immune restoration. This was assessed by evaluating T cell subset changes in individuals who received a salvage regimen of highly active antiretroviral therapy (HAART) after initially failing protease inhibitor monotherapy. Ten HIV-1-infected asymptomatic patients received a regimen of indinavir, zidovudine, and 3TC after failing saquinavir monotherapy. Changes in absolute numbers of naive, memory, and activated CD4+ and CD8+ T cells expressing a selection of CD45RA, CD62L, CD45RO, HLA-DR, and CD38 markers were monitored prospectively over 6 months. These measurements were correlated with plasma viral load along with alterations in a selected CD8+ V alpha/Vbeta T cell receptor (TCR) repertoire. Over 6 months there was a progressive increase in numbers of CD4+ memory (CD45RA-CD62L+) and naive (CD45RA+CD62L+) T cells, which displayed a modest inverse correlation with viral load. Two phases of CD8+ memory cell changes were identified, consisting of a transient increase in CD45RA+CD62L- numbers after 2 months and thereafter a progressive rise in CD45RA-CD62L+ cells until 6 months. A strong correlation existed between reduced viral load and loss of activated CD8+CD38+HLA-DR+ cell numbers. There was also a temporary broadening of the CD8+ V alpha/Vbeta TCR repertoire at 8 weeks, which became skewed after 6 months in parallel with reduced viral suppression. Closer analysis of naive and memory cell subset proportions in individual patients revealed that enlarged pools of naive subsets were evident in those patients with rebounds in viral load. Overall, drug-experienced patients responding to HAART displayed increased numbers of naive and memory CD4+ subsets, and reduced CD8+ cell activation with a loss of TCR skewing.

    View details for Web of Science ID 000073421600005

    View details for PubMedID 9591710

  • A pilot clinical trial of HIV antigen-pulsed allogeneic and autologous dendritic cell therapy in HIV-infected patients AIDS RESEARCH AND HUMAN RETROVIRUSES Kundu, S. K., Engleman, E., Benike, C., Shapero, M. H., Dupuis, M., van Schooten, W. C., Eibl, M., Merigan, T. C. 1998; 14 (7): 551-560

    Abstract

    A pilot study was carried out to assess the safety and antigen-presenting properties of allogeneic or autologous dendritic cells (DCs) in six HLA-A2+, HIV-infected patients. Allogeneic DCs obtained from the peripheral blood of HLA-identical, HIV-seronegative siblings were pulsed with recombinant HIV-1 MN gp160 or synthetic peptides corresponding to HLA-A2-restricted cytotoxic epitopes of envelope, Gag, and Pol proteins. The antigen-pulsed cells were infused intravenously six to nine times at monthly intervals and HIV-specific immune responses were monitored. One allogeneic DC recipient with a CD4+ T cell count of 460/mm3 showed increases in envelope-specific CTL- and lymphocyte-proliferative responses, as well as in IFN-gamma and IL-2 production. Another allogeneic DC recipient with a CD4+ T cell count of 434/mm3 also showed an increase in HIV envelope-specific lymphocyte-proliferative responses. A recipient of autologous DCs with a CD4+ T cell count of 730/mm3 showed an increase in peptide-specific lymphocyte-proliferative responses after three infusions. Three other allogeneic DC recipients with CD4+ T cell counts <410/mm3 did not show increases in their HIV-specific immune responses. No clinically significant adverse effects were noted in this study and CD4+ T cell numbers and plasma HIV-1 RNA detected by RT-PCR of all six patients were stable during the study period. Thus, both allogeneic and autologous DC infusions were well tolerated and in patients with normal or near normal CD4+ T cell counts administration of these antigen-pulsed cells enhanced the immune response to HIV. However, since no effect on viral load was observed there was no evidence that this approach provided clinical benefit.

    View details for Web of Science ID 000073421600004

    View details for PubMedID 9591709

  • Geographic and demographic differences in the frequency of human cytomegalovirus gB genotypes 1-4 in immunocompromised patients AIDS RESEARCH AND HUMAN RETROVIRUSES Zipeto, D., Hong, C., Gerna, G., Zavattoni, M., KATZENSTEIN, D., Merigan, T. C., Rasmussen, L. 1998; 14 (6): 533-536

    Abstract

    To test the hypothesis that human cytomegalovirus (CMV) gB genotype may differ with geographic origin or patient demographics, CMV DNA was amplified for gB typing from immunocompromised patients in Italy and Africa and compared with previously reported frequencies in California. Increased gB2 frequency occurred in Italian homosexual AIDS patients, as compared with both Italian heterosexual injection drug users with AIDS and heterosexual Zimbabwe AIDS patients. Occurrence of gB3 in Italy was higher in injection drug users than in homosexual AIDS patients. The incidence of gB4 was higher overall in the Italian as compared with the California patients. Therefore geographic and demographic differences in patients affect gB distribution and should be considered before associations of gB genotypes and virulence are made.

    View details for Web of Science ID 000072993500009

    View details for PubMedID 9566556

  • HIV-1 reverse transcriptase codon 215 mutation in plasma RNA: Immunologic and virologic responses to zidovudine JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Rey, D., Hughes, M., Pi, J. T., Winters, M., Merigan, T. C., Katzenstein, D. A. 1998; 17 (3): 203-208

    Abstract

    Treatment of HIV infection with zidovudine (ZDV) may select for changes in the genetic sequence of the viral reverse transcriptase (RT) that imparts drug resistance. The presence of a 2-bp mutation at codon 215 of RT (from threonine to phenylalanine or tyrosine) was assessed in plasma viral RNA in 85 subjects treated with ZDV in the AIDS Clinical Trials Group (ACTG) 175 virology substudy. Median CD4 cell numbers, HIV plasma RNA levels, and infectious titers of virus were significantly different over 56 weeks of treatment among 58 subjects with the wild-type threonine at codon 215 virus at study entry compared with the 27 subjects with mutations to phenylalanine or tyrosine (MUT) virus. Thirty percent (13 of 44 subjects) with wild-type virus at study entry developed a new codon 215 mutation. Genotypic resistance at codon 215 in plasma HIV RNA is associated with the subsequent immunologic and virologic failure of ZDV monotherapy in subjects with 200 to 500 CD4 cells/mm3.

    View details for Web of Science ID 000072312900003

    View details for PubMedID 9495218

  • Lymph node human immunodeficiency virus RNA levels and resistance mutations in patients receiving high-dose saquinavir JOURNAL OF INFECTIOUS DISEASES Schapiro, J. M., Winters, M. A., Vierra, M., Crawford, S., Merigan, T. C. 1998; 177 (2): 477-480

    Abstract

    The development of resistance mutations and human immunodeficiency virus (HIV) RNA levels were compared in lymph nodes and plasma of patients receiving antiretroviral therapy. Ten HIV-positive patients receiving high-dose saquinavir monotherapy (3600 or 7200 mg/day) underwent 14 lymph node biopsies before and during therapy. HIV RNA levels and appearance of resistance mutations to saquinavir were determined in simultaneous lymph node and plasma samples. HIV RNA levels were found to be consistently higher (mean, 3.16 log RNA copies; SD, 1.04; range, 2.23-5.59) in lymph nodes than in simultaneous plasma samples. Saquinavir therapy resulted in a reduction in HIV RNA levels in both plasma and lymph nodes. The presence or absence of a resistance mutation to saquinavir at codons 48 or 90 of the HIV-1 protease gene was identical in 13 of 14 biopsies, suggesting that resistance mutations to saquinavir appear within close temporal proximity in lymph nodes and plasma.

    View details for Web of Science ID 000071801500032

    View details for PubMedID 9466542

  • Generation of primary peptide-specific CD8(+) cytotoxic T-lymphocytes in vitro using allogeneic dendritic cells CELL TRANSPLANTATION Peshwa, M. V., Benike, C., Dupuis, M., Kundu, S. K., Engleman, E. G., Merigan, T. C., van Schooten, W. C. 1998; 7 (1): 1-9

    Abstract

    Dendritic cells (DC) are potent antigen-presenting cells (APC) capable of inducing strong T-cell-mediated immunity. Infusion of lymphoma-specific antigen-loaded autologous DC has been demonstrated to result in the generation of antigen-specific immunity and reduction in tumor burden in B-cell lymphoma patients. Cellular immunotherapy employing antigen-loaded DC could have a potential therapeutic impact in tumors and viral infections, including HIV infection. However, DC in HIV-infected individuals and breast cancer patients are believed to be functionally defective. Therefore, the potential of using allogeneic DC offers significant implications for DC immunotherapy in AIDS and immunocompromised cancer patients. To explore the potential of allogeneic DC therapy in vivo, we tested the ability of allogeneic DC to generate primary peptide-specific CD8+ cytotoxic T-lymphocyte (CTL) responses in vitro. Our results indicate that DC from HLA class I-matched individuals elicit primary immune responses in vitro using viral peptides as naive antigens. A primary peptide-specific immune response could also be detected even when only one HLA allele (HLA-A*0201) was matched between the allogeneic DC and T-lymphocytes. The ability to generate primary peptide-specific responses in vitro is strongly indicative of the in vivo therapeutic potential of allogeneic DC.

    View details for Web of Science ID 000072003100001

    View details for PubMedID 9489758

  • Risk for retinitis in patients with AIDS can be assessed by quantitation of threshold levels of cytomegalovirus DNA burden in blood JOURNAL OF INFECTIOUS DISEASES Rasmussen, L., Zipeto, D., Wolitz, R. A., Dowling, A., Efron, B., Merigan, T. C. 1997; 176 (5): 1146-1155

    Abstract

    Cytomegalovirus (CMV) retinitis in patients infected with human immunodeficiency virus (HIV) is a significant clinical problem. Seventy-five patients with CD4 T cell counts <100/mm3 were monitored prospectively every 2 months for CMV DNA burden. The target for DNA amplification was a 162-bp fragment from the CMV immediate early gene. CMV DNA burden, at levels of > or =320 in white blood cells or > or =32 in plasma (P = .001), particularly when sustained (P = .005 and .008, respectively), distinguished patients who developed retinitis from those who remained free of disease. Progression to retinitis was not consistently accompanied by increases in CMV burden, indicating that quantitation of CMV burden beyond threshold levels is not necessary to predict risk for development of retinitis. Virus isolation from WBC, but not urine, was also significantly associated with risk for retinitis (P = .001).

    View details for Web of Science ID A1997YD80900004

    View details for PubMedID 9359712

  • Effect of therapeutic immunization with recombinant gp160 HIV-1 vaccine on HIV-1 proviral DNA and plasma RNA: Relationship to cellular immune responses JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Kundu, S. K., KATZENSTEIN, D., Valentine, F. T., Spino, C., Efron, B., Merigan, T. C. 1997; 15 (4): 269-274

    Abstract

    Therapeutic vaccination has been proposed as a strategy to augment immune mechanisms to control viral replication and slow clinical progression of HIV infection to disease. Following recombinant gp160 (r-gp160) immunization in three clinical trials, plasma HIV-1 RNA and cellular proviral DNA were assessed by quantitative polymerase chain reaction (PCR) in 76 HIV-seropositive subjects with CD4+ T cell counts > or = 300/mm3. Immunization increased HIV-specific cellular immune responses (e.g., cytotoxic T lymphocyte [CTL] activities, lymphocyte proliferative responses); however, there were no significant effects of immunization or cellular immune responses on measures of plasma RNA or cellular DNA viral load.

    View details for Web of Science ID A1997YA52500004

    View details for PubMedID 9292585

  • Sequence and drug susceptibility of subtype C reverse transcriptase from human immunodeficiency virus type 1 seroconverters in Zimbabwe JOURNAL OF VIROLOGY Shafer, R. W., Eisen, J. A., Merigan, T. C., Katzenstein, D. A. 1997; 71 (7): 5441-5448

    Abstract

    Naturally occurring human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) variability has implications for the success of antiretroviral therapy. We determined the sequence of the polymerase-coding region of RT from virus isolates from 12 Zimbabwean individuals recently infected with HIV-1. The 12 RT sequences differed from the consensus B RT sequence at 10.5% of nucleotides and 5.8% of amino acids. Susceptibility testing of five isolates to zidovudine, didanosine, lamivudine, and nevirapine demonstrated susceptibilities similar to those of wild-type subtype B isolates. Phylogenetic analysis of 40 HIV-1 RT sequences, including the 12 Zimbabwean subtype C sequences, 11 subtype B sequences, and the 17 remaining published non-subtype B sequences showed sufficient intrasubtype RT sequence variation to differentiate subtype A, B, C, and D isolates. Five recently reported subtype C RT sequences from India grouped with the Zimbabwean subtype C sequences but had significantly less intraisolate sequence variation. Both intra- and intersubtype RT comparisons were notable for extraordinarily high ratios of synonymous to nonsynonymous differences. Although substitutions in the HIV-1 RT gene are limited by functional constraints, variation between RT sequences demonstrates phylogenetic relationships that parallel env and gag gene variation.

    View details for Web of Science ID A1997XD82900068

    View details for PubMedID 9188616

  • Heterogeneity of cytokine functions in HIV infection IMMUNOLOGY Kundu, S. K., Merigan, T. C. 1997; 91 (2): 234-238

    Abstract

    Immunological responses, especially cytokines, play important roles in determining the persistence of infectious agents in chronic diseases. Th1 responses enhance cellular immunity to control infection whereas Th2 immune responses down-regulate these effector immune responses. It has been suggested that the Th1 to Th2 switch is involved in human immunodeficiency virus (HIV) disease progression. We studied the regulatory role of interleukin-4 (IL-4; Th2 response) on interferon-gamma (IFN-gamma; Th1 response) in HIV infection and its role in the generation of HIV-specific cytotoxic T lymphocytes (CTL) in an in vitro system. Forty HIV-infected, asymptomatic individuals and 20 HIV-seronegative individuals were included in this study. Peripheral blood mononuclear cells were stimulated with phytohaemagglutinin and tetanus toxoid in the presence or absence of IL-4 to determine the effect of IL-4 on IFN-gamma production and HIV-Env-specific CTL activity. IL-4 showed a dual effect on IFN-gamma production in HIV patients. IL-4 down-regulated IFN-gamma production in HIV-seronegative individuals and in 55% of HIV patients whereas it stimulated IFN-gamma production in 45% of HIV patients. IL-4 increased HIV-Env-specific CTL activity in five of seven patients of the latter group. IL-4 has multiple biological activities, e.g. IL-4 inhibits IFN-gamma production as well as stimulates CTL generation which in turn produces IFN-gamma. Understanding the biological significance of these interactions is of importance for immunotherapeutic approaches against HIV infection.

    View details for Web of Science ID A1997XD01400011

    View details for PubMedID 9227322

  • Human immunodeficiency virus type 1 reverse transcriptase genotype and drug susceptibility changes in infected individuals receiving dideoxyinosine monotherapy for 1 to 2 years ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Winters, M. A., Shafer, R. W., Jellinger, R. A., Mamtora, G., Gingeras, T., Merigan, T. C. 1997; 41 (4): 757-762

    Abstract

    The genetic mechanisms of human immunodeficiency virus type 1 (HIV-1) resistance to dideoxyinosine (ddI) in vivo have been described based on data from primary HIV-1 isolates. To better define the spectrum of HIV-1 reverse transcriptase (RT) changes occurring during ddI therapy, we determined the genotype and ddI susceptibility of the RT gene of HIV RNA isolated from the plasma of 23 patients who had received 1 to 2 years (mean, 87 +/- 16 weeks) of ddI monotherapy. Population-based sequencing of plasma virus showed that 12 of 23 (52%) patients developed known ddI resistance mutations: L74V (7 patients), K65R (2 patients), L74V with M184V (3 patients), and L74V with K65R (1 patient). Five patients developed one or more known zidovudine resistance mutations (at codons 41, 67, 70, 215, and/or 219) during the study. Other amino acid substitutions were found, but only S68G and L210W occurred in more than one patient. Studies of sensitivity to ddI were performed on population-based recombinant-virus stocks generated by homologous recombination between a plasmid containing an HXB2 clone with the RT gene deleted and RT-PCR products of the RT genes from patients' plasma RNA. The sequences of the virus stocks produced by this procedure were typically identical to the sequence of the input PCR product from plasma RNA. Both an MT-2 cell-based culture assay and a cell-free virion-associated RT inhibition assay showed that viruses possessing an L74V and/or M184V mutation or a K65R mutation had reduced sensitivity to ddI. Viruses without these specific mutations had no change in sensitivity to ddI. The results presented here show that the spectrum of RT mutations in a population of patients on ddI monotherapy is more complex than previously described. The development of multiple mutational patterns, including those that confer resistance to other nucleoside analogs, highlights the complexity of using the currently available nucleoside analogs for antiretroviral therapy.

    View details for Web of Science ID A1997WR16600008

    View details for PubMedID 9087484

  • A novel approach to assessing the drug susceptibility and replication of human immunodeficiency virus type 1 isolates JOURNAL OF INFECTIOUS DISEASES Jellinger, R. M., Shafer, R. W., Merigan, T. C. 1997; 175 (3): 561-566

    Abstract

    Human immunodeficiency virus type 1 (HIV-1) drug susceptibility testing is often curtailed because such testing is expensive and time consuming. A colorimetric tetrazolium dye method previously used for high-throughput antiviral drug screening was adapted to assess the susceptibility of 16 HIV-1 isolates to zidovudine, didanosine, lamivudine, and nevirapine in MT-2 cells. Cell viability was assessed colorimetrically, and all measurements and calculations were automated. Each HIV-1 isolate was tested in > or = 5 assays to determine the reproducibility of the assay in HIV-1 isolates with known reverse-transcriptase mutations. The drug susceptibility of several mutant HIV-1 strains whose drug susceptibilities had not previously been well defined was also determined. Data on HIV-1 replication from the susceptibility assays indicated that some mutant HIV-1 isolates may have been less cytopathic in MT-2 cells than wild type HIV-1 isolates.

    View details for Web of Science ID A1997WK41100008

    View details for PubMedID 9041326

  • Comparison of QIAamp HCV kit spin columns, silica beads, and phenol-chloroform for recovering human immunodeficiency virus type 1 RNA from plasma JOURNAL OF CLINICAL MICROBIOLOGY Shafer, R. W., Levee, D. J., Winters, M. A., Richmond, K. L., Huang, D., Merigan, T. C. 1997; 35 (2): 520-522

    Abstract

    Human immunodeficiency virus type 1 (HIV-1) pol mutations are responsible for HIV-1 resistance to current antiretroviral drugs. HIV-1 RNA extraction with QIAamp HCV kit spin columns (Qiagen, Chatsworth, Calif.) followed by reverse transcription-PCR successfully recovered a 1,008-bp pol fragment from the plasma of 31 of 34 HIV-1-infected patients that was suitable for sequencing and recombinant-virus studies. The minimum HIV-1 RNA concentration required for gene recovery was 30 to 40 copies/ml, which was similar to the minimal HIV-1 RNA concentration required when phenol-chloroform or silica beads are used for RNA extraction.

    View details for Web of Science ID A1997WD08200042

    View details for PubMedID 9003633

  • Allogeneic dendritic cell induction of HIV-specific cytotoxic T lymphocyte responses from T cells of HIV type 1-infected and uninfected individuals AIDS RESEARCH AND HUMAN RETROVIRUSES Dupuis, M., Peshwa, M. V., Benike, C., Kundu, S. K., Engleman, E. G., VANSCHOOTEN, W. C., Merigan, T. C. 1997; 13 (1): 33-39

    Abstract

    The potential benefit of T cell-based vaccination for HIV-1 infection remains to be determined. Cytotoxic T lymphocytes (CTLs) appear to clear substantial populations of HIV-1 virus in vivo, although CTL activity may contribute to the decline in CD4+ T cell count observed in the course of the disease. To investigate further the role of specific CTL responses in the control of HIV-1 replication, we raised primary CTL lines against a panel of conserved HIV-1 epitopes using blood-derived dendritic cells as antigen-presenting cells (APCs). Specific primary human CTL responses were induced against HLA-A*0201-restricted peptides with dendritic cells from HIV-1-seronegative donors. This method of immunization elicited cytotoxic activities capable of recognizing endogenously processed antigen. The CTL induction protocol was extended in order to explore the capacity of HLA-matched allogeneic dendritic cells to evoke novel CTL responses in T cells from an HIV-seropositive asymptomatic individual. Allogeneic peptide-pulsed dendritic cells from a healthy sibling were capable of eliciting a CTL response directed against an HIV epitope (env814: SLLNATDIAV) that was initially not detected in the CTL effector population of the HIV-1-infected patient. The possibility of manipulating CTL specificity directed against multiple conserved HIV-1 epitopes represents a significant step in the evaluation of T cell-based vaccination for treatment of disease.

    View details for Web of Science ID A1997WA16700006

    View details for PubMedID 8989425

  • Patient compliance and drug failure in protease inhibitor monotherapy JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Vanhove, G. F., Schapiro, J. M., Winters, M. A., Merigan, T. C., Blaschke, T. F. 1996; 276 (24): 1955-1956

    View details for Web of Science ID A1996VY68900024

    View details for PubMedID 8971062

  • Genotypic and phenotypic changes during culture of a multinucleoside-resistant human immunodeficiency virus type 1 strain in the presence and absence of additional reverse transcriptase inhibitors ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Shafer, R. W., Winters, M. A., Iversen, A. K., Merigan, T. C. 1996; 40 (12): 2887-2890

    Abstract

    The observation that human immunodeficiency virus type 1 (HIV-1) mutations conferring resistance to one reverse transcriptase (RT) inhibitor may suppress resistance to other RT inhibitors provides a rationale for treating HIV-1 with certain RT inhibitor combinations. We examined phenotypic and genotypic changes during culture of a multinucleoside (zidovudine, didanosine, zalcitibine, and stavudine)-resistant HIV-1 strain with and without additional RT inhibitors (nevirapine and lamivudine). The development of nevirapine or lamivudine resistance by the multinucleoside-resistant strain was not accompanied by a reduction in zidovudine or didanosine resistance.

    View details for Web of Science ID A1996VW22100041

    View details for PubMedID 9124861

  • A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. AIDS Clinical Trials Group Study 175 Study Team. New England journal of medicine Hammer, S. M., Katzenstein, D. A., Hughes, M. D., Gundacker, H., Schooley, R. T., Haubrich, R. H., Henry, W. K., Lederman, M. M., Phair, J. P., Niu, M., Hirsch, M. S., Merigan, T. C. 1996; 335 (15): 1081-1090

    Abstract

    This double-blind study evaluated treatment with either a single nucleoside or two nucleosides in adults infected with human immunodeficiency virus type 1 (HIV-1) whose CD4 cell counts were from 200 to 500 per cubic millimeter.We randomly assigned 2467 HIV-1--infected patients (43 percent without prior antiretroviral treatment) to one of four daily regimens: 600 mg of zidovudine; 600 mg of zidovudine plus 400 mg of didanosine; 600 mg of zidovudine plus 2.25 mg of zalcitabine; or 400 mg of didanosine. The primary end point was a > or = 50 percent decline in the CD4 cell count, development of the acquired immunodeficiency syndrome (AIDS), or death.Progression to the primary end point was more frequent with zidovudine alone (32 percent) than with zidovudine plus didanosine (18 percent; relative hazard ratio, 0.50; P<0.001), zidovudine plus zalcitabine (20 percent; relative hazard ratio, 0.54; P<0.001), or didanosine alone (22 percent; relative hazard ratio, 0.61; P<0.001). The relative hazard ratios for progression to an AIDS-defining event or death were 0.64 (P=0.005) for zidovudine plus didanosine, as compared with zidovudine alone, 0.77 (P=0.085) for zidovudine plus zalcitabine, and 0.69 (P=0.019) for didanosine alone. The relative hazard ratios for death were 0.55 (P=0.008), 0.71 (P=0.10), and 0.51 (P=0.003), respectively. For zidovudine plus zalcitabine, the benefits were limited to those without previous treatment.Treatment with zidovudine plus didanosine, zidovudine plus zalcitabine, or didanosine alone slows the progression of HIV disease and is superior to treatment with zidovudine alone. Antiretroviral therapy can improve survival in patients with 200 to 500 CD4 cells per cubic millimeter.

    View details for PubMedID 8813038

  • The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter NEW ENGLAND JOURNAL OF MEDICINE Katzenstein, D. A., Hammer, S. M., Hughes, M. D., Gundacker, H., Jackson, J. B., Fiscus, S., Rasheed, S., Elbeik, T., REICHMAN, R., Japour, A., Merigan, T. C., Hirsch, M. S. 1996; 335 (15): 1091-1098

    Abstract

    We studied measures of human immunodeficiency virus (HIV) replication, the viral phenotype, and immune function (CD4 cell counts) and the relation of changes in these indicators to clinical outcomes in a subgroup of patients in a controlled trial of early antiretroviral treatment for HIV, the AIDS Clinical Trials Group Study 175.The 391 subjects, each of whom entered the study with a single screening CD4 cell count of 200 to 500 per cubic millimeter, were randomly assigned to receive zidovudine alone, didanosine alone, zidovudine plus didanosine, or zidovudine plus zalcitabine. Plasma concentrations of HIV RNA were assessed in 366 subjects, and viral isolates from 332 subjects were assayed for the presence of the syncytium-inducing phenotype.After eight weeks, the mean (+/-SE) decrease from base line in the concentration of HIV RNA, expressed as the change in the base 10 log of the number of copies per milliliter, was 0.26+/-0.06 for patients treated with zidovudine alone, 0.65+/-0.07 for didanosine alone, 0.93+/-0.10 for zidovudine plus didanosine, and 0.89+/-0.06 for zidovudine plus zalcitabine (P<0.001 for each of the pairwise comparisons with zidovudine alone). Multivariate proportional-hazards models showed that higher base-line concentrations of plasma HIV RNA, less suppression of plasma HIV RNA by treatment, and the presence of the syncytium-inducing phenotype were significantly associated with an increased risk of progression to the acquired immunodeficiency syndrome and death. After adjustment for these measures of viral replication and for the viral phenotype, CD4 cell counts were not significant predictors of clinical outcome.Both the risk of the progression of HIV disease and the efficacy of antiretroviral therapy are strongly associated with the plasma level of HIV RNA and with the viral phenotype. The changes in the plasma concentration of HIV RNA predict the changes in CD4 cell counts and survival after treatment with reverse-transcriptase inhibitors.

    View details for Web of Science ID A1996VN39900002

    View details for PubMedID 8813039

  • Human immunodeficiency virus reverse transcriptase codon 215 mutations diminish virologic response to didanosine-zidovudine therapy in subjects with non-syncytium-inducing phenotype JOURNAL OF INFECTIOUS DISEASES Holodniy, M., KATZENSTEIN, D., Mole, L., Winters, M., Merigan, T. 1996; 174 (4): 854-857

    Abstract

    Eight zidovudine-experienced subjects received zidovudine and didanosine for 30 weeks followed by 30 weeks of didanosine monotherapy. At study entry, plasma from 4 subjects had human immunodeficiency virus RNA pol T215Y/F mutant and 4 had codon 215 wild type. All 8 subjects had non-syncytium-inducing virus phenotype. Sustained 10-fold decreases in plasma RNA levels were seen only in subjects who initially had 215 wild type RNA, despite the development of a T215Y/F mutation during combination therapy. Virologic and immunologic benefits were maintained in this group with didanosine monotherapy. No subject developed a pol L74V codon mutation. Significant differences in plasma virus load and CD4 cell responses were seen in this zidovudine-didanosine combination pilot study relative to codon 215 genotype.

    View details for Web of Science ID A1996VK04500027

    View details for PubMedID 8843229

  • Multiple cerebral lesions complicating therapy with interleukin-2 NEUROLOGY Karp, B. I., Yang, J. C., Khorsand, M., Wood, R., Merigan, T. C. 1996; 47 (2): 417-424

    Abstract

    We reviewed the records and radiologic studies of eight patients who developed new focal neurologic abnormalities while receiving interleukin-2 (IL2)-based immunotherapy for malignancy or HIV infection. Initial confusion and delirium in the patients evolved into coma, ataxia, hemiparesis, seizures, and cortical syndromes including aphasia, apraxia, and cortical blindness. Imaging studies showed multiple white and gray matter lesions with a predilection for the occipital poles, centrum semiovale, and cerebellum. After cessation of IL2 treatment, seven patients improved to normal or near-normal neurologic function paralleled by resolution of the lesions on scans. One patient improved only minimally. Possible etiologies for the lesions include an IL2-induced cerebral vasculopathy, a direct toxic effect of IL2, or immunologically mediated damage.

    View details for Web of Science ID A1996VC63400017

    View details for PubMedID 8757014

  • Zidovudine resistance reverse transcriptase mutations during didanosine monotherapy JOURNAL OF INFECTIOUS DISEASES Shafer, R. W., Winters, M. A., Jellinger, R. M., Merigan, T. C. 1996; 174 (2): 448-449

    View details for Web of Science ID A1996UZ09300041

    View details for PubMedID 8699089

  • Extensive polymorphisms observed in HIV-1 clade B protease gene using high-density oligonucleotide arrays NATURE MEDICINE Kozal, M. J., Shah, N., Shen, N. P., Yang, R., FUCINI, R., Merigan, T. C., Richman, D. D., Morris, D., Hubbell, E. R., Chee, M., Gingeras, T. R. 1996; 2 (7): 753-759

    Abstract

    Naturally occurring mutations in HIV-1-infected patients have important implications for therapy and the outcome of clinical studies. However, little is known about the prevalence of mutations that confer resistance to HIV-1 protease inhibitors in isolates derived from patients naive for such inhibitors. In the first clinical application of high-density oligonucleotide array sequencing, the sequences of 167 viral isolates from 102 patients have been determined. The DNA sequence of USA HIV-1 clade B proteases was found to be extremely variable and 47.5% of the 99 amino acid positions varied. This level of amino acid diversity is greater than that previously known for all worldwide HIV-1 clades combined (40%). Many of the amino acid changes that are known to contribute to drug resistance occurred as natural polymorphisms in isolates from patients who had never received protease inhibitors.

    View details for Web of Science ID A1996UU68000030

    View details for PubMedID 8673920

  • The effect of high-dose saquinavir on viral load and CD4(+) T-cell counts in HIV-infected patients ANNALS OF INTERNAL MEDICINE Schapiro, J. M., Winters, M. A., Stewart, F., Efron, B., Norris, J., Kozal, M. J., Merigan, T. C. 1996; 124 (12): 1039-1050

    Abstract

    To evaluate the efficacy and safety of high-dose therapy with the human immunodeficiency virus (HIV) protease inhibitor saquinavir and to establish the duration of the effect of this therapy.Open-label study.Clinical research referral center.40 adults with human immunodeficiency virus type 1 (HIV-1) infection and CD4+ T-cell counts of 200 to 500 cells/mm3.Monotherapy with 3600 mg or 7200 mg of saquinavir per day, in six divided doses, for 24 weeks.Patients were monitored for adverse events and were evaluated monthly for CD4+ T-cell count, HIV-1 viral load (as measured by reverse transcriptase polymerase chain reaction [PCR] for plasma HIV RNA levels), immune-complex-disassociated p24 antigen levels, peripheral blood mononuclear cell viral DNA levels (as measured by PCR), and resistance mutations to saquinavir. Quantitative peripheral blood mononuclear cell cultures were also done every 2 months.The low-dose saquinavir regimen (3600 mg/d) resulted in a maximal mean decrease in plasma HIV RNA levels of 1.06 log RNA copies/mL of plasma and a mean maximal increase in CD4 counts of 72 cells/mm3. At week 24, the plasma HIV RNA level remained 0.48 log RNA copies/mL of plasma lower than baseline (P < 0.001) and the CD4 count remained 31 cells/mm3 higher than baseline (P = 0.165). The high-dose saquinavir regimen (7200 mg/d) produced a mean maximal decrease in the plasma HIV RNA level of 1.34 log RNA copies/mL of plasma and a mean maximal increase in CD4 count of 121 cells/mm3. At week 24, the plasma HIV RNA level remained 0.85 log RNA copies/mL of plasma lower than baseline (P < 0.001) and the CD4 count remained 82 cells/mm3 higher than baseline (P = 0.002). The high-dose regimen produced a greater reduction in plasma HIV RNA level (P = 0.08), a greater reduction in peripheral blood mononuclear cell cultures (P = 0.008), and a greater increase in CD4 count (P = 0.002) than did the low-dose regimen. Higher plasma drug concentrations in individual patients correlated with greater reductions in plasma HIV RNA levels over the two doses. Nine patients receiving the low-dose regimen and four patients receiving the high-dose regimen developed key saquinavir resistance mutations. Adverse reactions, most commonly gastrointestinal problems and elevated serum aminotransferase levels, were more common in patients receiving the high-dose regimen, but most adverse events were mild and all were reversible.Saquinavir is a potent antiviral agent that has a favorable toxicity profile at high doses. Higher doses produce a greater and more durable suppression of viral load and elevation in CD4+ T-cell counts and may delay the development of resistance mutations. Therapy with high-dose saquinavir alone or in combination with other antiretroviral agents should be investigated further.

    View details for Web of Science ID A1996UQ65800003

    View details for PubMedID 8633817

  • A randomized, placebo-controlled study of the immunogenicity of human immunodeficiency virus (HIV) rgp160 vaccine in HIV-infected subjects with >=400/mm(3) CD4 T lymphocytes (AIDS clinical trials group protocol 137) JOURNAL OF INFECTIOUS DISEASES Valentine, F. T., Kundu, S., Haslett, P. A., KATZENSTEIN, D., Beckett, L., Spino, C., Borucki, M., Vasquez, M., Smith, G., Korvick, J., Kagan, J., Merigan, T. C. 1996; 173 (6): 1336-1346

    Abstract

    Immune responses provoked by human immunodeficiency virus (HIV) infection ultimately are insufficient to control the disease and do not include strong lymphocyte-proliferative responses to HIV antigens or antibodies to many viral epitopes. A randomized double-blind, placebo-controlled trial evaluated the immunogenicity of recombinant HIV envelope vaccine (rgp160) in HIV-infected subjects with > or = 400/mm3 CD4 T cells. Controls received hepatitis B vaccine. Of subjects receiving rgp160, 98% developed lymphocyte-proliferative responses to the immunogen, 33% to a different envelope protein, and 56% and 60% to p24 and p66, respectively. All doses of vaccine (20, 80, 320, 1280 microgram) induced new responses. New antibodies to epitopes on rgp160 developed only in recipients of higher doses of rgp160. CD4 T cell percentages declined less rapidly in recipients of rgp160 than in controls. Vaccination of HIV-infected subjects with rgp160 results in cellular and humoral immune responses to HIV that infection itself had not stimulated.

    View details for Web of Science ID A1996UM11500006

    View details for PubMedID 8648205

  • Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine NEW ENGLAND JOURNAL OF MEDICINE Collier, A. C., COOMBS, R. W., Schoenfeld, D. A., Bassett, R. L., Timpone, J., Baruch, A., Jones, M., Facey, K., Whitacre, C., MCAULIFFE, V. J., Friedman, H. M., Merigan, T. C., Reichman, R. C., Hooper, C., Corey, L. 1996; 334 (16): 1011-1017

    Abstract

    In patients with human immunodeficiency virus (HIV) infection, combined treatment with several agents may increase the effectiveness of antiviral therapy. We studied the safety and efficacy of saquinavir, an HIV-protease inhibitor, given with one or two nucleoside antiretroviral agents, as compared with the safety and efficacy of a combination of two nucleosides alone.In this double-blind trial, patients with HIV infection were randomly assigned to receive either saquinavir (1800 mg per day) plus both zidovudine (600 mg per day) and zalcitabine (2.25 mg per day) or zidovudine plus either saquinavir or zalcitabine. The 302 patients enrolled had CD4+ counts of 50 to 300 cells per cubic millimeter and had previously received zidovudine for a median of 27 months. The study lasted 24 weeks, with an optional double-blind extension period of an additional 12 to 32 weeks.Ninety-six percent of the patients completed the 24-week study. In all three treatment groups, CD4+ cell counts rose at first and then fell gradually. The normalized area under the curve for the CD4+ count was greater with the three-drug combination than with either saquinavir and zidovudine (P=0.017) or zalcitabine and zidovudine (P<0.001). There were significantly greater reductions in plasma HIV with the three-drug combination than with the other regimens when peripheral-blood mononuclear cells were cultured for HIV and HIV RNA was assessed, and there were greater decreases in serum neopterin and beta2-microglobulin levels. There were no major differences in toxic effects among the three treatments.Treatment with saquinavir, zalcitabine, and zidovudine was well tolerated. This drug combination reduced HIV-1 replication, increased CD4+ cell counts, and decreased levels of activation markers in serum more than did treatment with zidovudine and either saquinavir or zalcitabine. Studies are warranted to evaluate whether the three-drug combination will reduce morbidity and mortality.

    View details for Web of Science ID A1996UE73300002

    View details for PubMedID 8598838

  • Polyethylene glycol-modified interleukin-2 and thymosin alpha(1) in human immunodeficiency virus type 1 infection JOURNAL OF INFECTIOUS DISEASES Ramachandran, R., Katzenstein, D. A., Winters, M. A., Kundu, S. K., Merigan, T. C. 1996; 173 (4): 1005-1008

    Abstract

    The safety and antiviral effects of polyethylene glycolated interleukin-2 (PEG-IL-2) and thymosin alpha 1 in addition to zidovudine were studied in 12 human immunodeficiency virus (HIV)-infected subjects with 50-250 CD4 T cells/mm3. PEG-IL-2 was administered by intravenous infusions every 2 weeks at 10(6) IU/m2 for 20 weeks. Thymosin alpha 1 was administered subcutaneously at 400 microgram/m2 after four doses of PEG-IL-2, escalating to 1600 microgram/m2 weekly for an additional 2 months. Significant elevations of CD4 T cell numbers of 30%-40% were seen after PEG-IL-2 infusions, but no additional increase in CD4 cell count was observed with thymosin alpha 1. Virologic monitoring by polymerase chain reaction quantitation of proviral DNA and plasma RNA and p24 antigen assays showed no evidence of increased HIV activation during PEG-IL-2 or thymosin alpha 1 therapy. Patients tolerated both PEG-IL-2 and thymosin alpha 1 without significant toxicities.

    View details for Web of Science ID A1996UB27400032

    View details for PubMedID 8603940

  • The laboratory in managing HIV infection MEDICAL JOURNAL OF AUSTRALIA Dwyer, D. E., Adelstein, S., Cunningham, A. L., Merigan, T. C. 1996; 164 (5): 301-303

    Abstract

    The CD4 cell count is a useful guide to the clinical stages of HIV infection, although it is only an indirect measure of viral activity. More direct measures of viral load will eventually become part of clinical practice.

    View details for Web of Science ID A1996TY14400015

    View details for PubMedID 8628167

  • The prognostic significance of serum viral load, codon 215 reverse transcriptase mutation and CD4+ T cells on progression of HIV disease in a double-blind study of thymopentin AIDS Merigan, T. C., Hirsch, R. L., Fisher, A. C., Meyerson, L. A., Goldstein, G., Winters, M. A. 1996; 10 (2): 159-165

    Abstract

    To determine in asymptomatic HIV-infected subjects the prognostic value of virion reverse transcriptase (RT) codon 215 mutation, serum HIV RNA level, CD4+ T-cell count and immune complex dissociated (ICD) p24 level. The retrospective evaluation of thymopentin treatment effect on subjects in high risk groups for progression was a secondary objective.Zidovudine (ZDV)-experienced asymptomatic HIV-infected subjects (n = 352) who had been enrolled in a 48-week placebo-controlled double-blind trial of thymopentin treatment were studied.Post hoc analyses were conducted to determine which subjects at study entry were at greater risk for progression to AIDS-related complex (ARC), AIDS or death, and to determine the effect of treatment on these subjects. Four potential prognostic variables (virion RT codon 215 mutation, circulating HIV virion RNA copies, CD4+ T-cell count, and ICD p24) were evaluated by dichotomizing subjects for each variable based on the median of the observed values. CD4+ T-cell count was evaluated prospectively, whereas frozen samples were evaluated under blinded conditions for the other variables after the study was completed.The presence of the codon 215 mutation [P = 0.044; relative hazard (RH), 2.6], > or = 20,000 HIV RNA copies/ml (P = 0.002; RH, 5.5), and < 350 CD4+ cells 10(6)/l (P = 0.042; RH, 2.2) were prognostic factors, and > or = 30 pg/ml ICD p24 level (P = 0.52; RH, 1.4) was not a prognostic factor in predicting progression. Subjects were prestratified by previous ZDV use (< or = 6 or > 6 months). Across both strata thymopentin delayed treatment progression to ARC, AIDS, or death (P = 0.015; RH, 3.0). This effect was magnified in the ZDV-experienced subjects at greater risk, where thymopentin delayed progression compared to placebo in the presence of the codon 215 mutation (P = 0.007; RH, 10.1), > or = 20,000 RNA copies/ml (P = 0.012; RH, 8.9), and CD4+ T-cell count < 350 x 10(6)/l (P = 0.005; RH, 10.4).Codon 215 mutation, serum HIV RNA and CD4 T-cell count are independent predictors of progression in ZDV-experienced asymptomatic subjects. Furthermore, thymopentin delays HIV disease progression in the presence of a key ZDV resistance mutation as well as high viral load and low CD4+ T-cell counts.

    View details for Web of Science ID A1996TW20500005

    View details for PubMedID 8838703

  • Multidrug-resistant human immunodeficiency virus type 1 strains resulting from combination antiretroviral therapy JOURNAL OF VIROLOGY Iversen, A. K., Shafer, R. W., Wehrly, K., Winters, M. A., Mullins, J. I., Chesebro, B., Merigan, T. C. 1996; 70 (2): 1086-1090

    Abstract

    Multidrug-resistant human immunodeficiency virus type 1 (HIV-1) strains with reverse transcriptase (RT) mutations at codons A62-->V, V75-->I, F77-->L, F116-->Y, and Q151-->M have been reported in patients receiving combination therapy with zidovudine (AZT) and didanosine (ddI). Infectious clones with each mutation alone, all five mutations together, and various combinations of mutations were created by site-directed mutagenesis. Mutation Q151-->M conferred partial resistance to AZT, ddI, zalcitibine, and stavudine, whereas a combination of four mutations conferred increased resistance to AZT, ddI, zalcitibine, and stavudine. The positions of residues 75, 77, and 151 in the three-dimensional crystal structure of HIV-1 RT suggest that these residues may affect the ability of the enzyme to discriminate between deoxynucleoside triphosphates and nucleoside analog RT inhibitors. Replication experiments showed that clones with mutation F77-->L but without V75-->I (HIV-1(77), HIV-1(77,151), and HIV-1(77,116,151) had attenuated growth compared with that of the original HIV-1NL4-3 strain and strains containing mutations at both positions 75 and 77 (HIV-1(75,77,151) and HIV-1(75,77,116,15)). Sequence analysis of viral RNA and proviral DNA from several patients indicated that RT mutations developed in a sequential and cumulative pattern over the course of a 2- to 4-year observation period. The present results suggest that drug resistance and viral replicative capacity both may play a role in selection of HIV-1 RT mutations.

    View details for Web of Science ID A1996TP52600049

    View details for PubMedID 8551567

  • Clinical treatment. AIDS Cooper, D. A., Merigan, T. C. 1996; 10: S133-4

    View details for PubMedID 8883620

  • A QUARTER-CENTURY OF ANTIVIRAL THERAPY NEW ENGLAND JOURNAL OF MEDICINE Merigan, T. C. 1995; 333 (25): 1704-1705

    View details for Web of Science ID A1995TL40100009

    View details for PubMedID 7477225

  • The tolerability and pharmacokinetics of N-butyl-deoxynojirimycin in patients with advanced HIV disease (ACTG 100). The AIDS Clinical Trials Group (ACTG) of the National Institute of Allergy and Infectious Diseases. Journal of acquired immune deficiency syndromes and human retrovirology Tierney, M., Pottage, J., Kessler, H., Fischl, M., Richman, D., Merigan, T., Powderly, W., Smith, S., Karim, A., Sherman, J. 1995; 10 (5): 549-553

    Abstract

    Twenty-nine patients were enrolled in a phase I dose-escalating tolerance trial of N-butyl-deoxynojirimycin, an alpha-glucosidase I inhibitor that inhibits human immunodeficiency virus (HIV)-1 replication by altering glycosylation of gp120. Dosing was begun at 8 mg/kg/day and subsequent doses were 16, 32, 48, and 64 mg/kg/day. The maximum tolerated dose was not achieved because of slow accrual and because the study was stopped after the finding of cataracts in initial long-range rat toxicology studies. These cataracts were later shown to be transient and not found in other animals. The most common side effects were gastrointestinal, with diarrhea and flatulence occurring in most subjects, which seemed to partially improve on a modified diet that excluded complex carbohydrates. Grade III elevations in liver function tests were seen in two patients. Grade III leukopenia and neutropenia were seen in seven patients, but were only severe enough in two to require discontinuation. No significant trends in CD4 cell counts or HIV-1 p24 levels were noted.

    View details for PubMedID 8548334

  • SAFETY, PHARMACOKINETICS, AND ANTIVIRAL RESPONSE OF CD4-IMMUNOGLOBULIN-G BY INTRAVENOUS BOLUS IN AIDS AND AIDS-RELATED COMPLEX JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Collier, A. C., COOMBS, R. W., KATZENSTEIN, D., Holodniy, M., Gibson, J., Mordenti, J., Izu, A. E., Duliege, A. M., Ammann, A. J., Merigan, T., Corey, L. 1995; 10 (2): 150-156

    Abstract

    To assess the safety, pharmacokinetics, and antiviral effects of intravenous recombinant CD4 immunoglobulin G (CD4-IgG), a 12-week Phase One study with an optional maintenance phase was performed. Twenty-two subjects with advanced human immunodeficiency virus (HIV) infection were enrolled; 15 subjects completed the initial 12 weeks. CD4-IgG doses were 30, 100, or 300 micrograms/kg weekly; 1,000 micrograms/kg once, twice, or three times per week; or 3,000 micrograms/kg twice weekly. Serum concentrations of CD4-IgG increased linearly with dose, with average peak serum concentrations of 22 micrograms/ml with 1,000 micrograms/kg. CD4-IgG was well tolerated; one patient had self-limited tachycardia and flushing associated with CD4-IgG therapy. No changes were seen in CD4 cell counts, hematologic or coagulation studies, serum chemistries, HIV p24 antigen titers, or plasma HIV titers. No subject developed anti-CD4 antibodies. HIV isolates from five patients had IC90 values that were higher than the peak concentrations of CD4-IgG achieved in those patients. Additional studies that achieve higher CD4-IgG concentrations are necessary to evaluate the antiviral activity of this compound.

    View details for Web of Science ID A1995RW33000006

    View details for PubMedID 7552478

  • HUMAN CYTOMEGALOVIRUS (CMV) DNA IN PLASMA REFLECTS QUANTITY OF CMV DNA PRESENT IN LEUKOCYTES JOURNAL OF CLINICAL MICROBIOLOGY Zipeto, D., Morris, S., Hong, C., Dowling, A., Wolitz, R., Merigan, T. C., Rasmussen, L. 1995; 33 (10): 2607-2611

    Abstract

    A quantitative DNA amplification assay for human cytomegalovirus (CMV) DNA has been used to evaluate the relationship between quantities of CMV DNA in plasma and those in infected leukocytes (WBC) from human immunodeficiency virus-infected patients. The target sequence for DNA amplification was a region of the immediate-early 1 gene of CMV. The quantitation assay uses an internal control that is coamplified with each patient sample DNA and contains a sequence for detection by colorimetric hybridization with the same bases, but in different order than in the CMV immediate-early 1 region used for hybridization of amplified patient sample DNA. Results showed that patients with CMV disease had more CMV DNA in both WBC and plasma than those without disease. However, in this study, copy numbers of CMV DNA in WBC were higher than those in plasma. The gB and gH variants were the same in plasma and WBC.

    View details for Web of Science ID A1995RV56500015

    View details for PubMedID 8567891

  • PERSISTENCE OF ATTENUATED REV GENES IN A HUMAN-IMMUNODEFICIENCY-VIRUS TYPE 1-INFECTED ASYMPTOMATIC INDIVIDUAL JOURNAL OF VIROLOGY Iversen, A. K., Shpaer, E. G., Rodrigo, A. G., Hirsch, M. S., Walker, B. D., Sheppard, H. W., Merigan, T. C., Mullins, J. I. 1995; 69 (9): 5743-5753

    Abstract

    With the goal of examining the functional diversity of human immunodeficiency virus type 1 (HIV-1) env genes within the peripheral blood mononuclear cells of an asymptomatic individual, we substituted four complete env genes into the replication-competent NL4-3 provirus. Despite encoding full-length open reading frames for gp120 and gp41 and the second coding exon of tat and rev, each chimera was replication defective. Site-directed mutagenesis of codon 78 in the Rev activation domain (from a hitherto unique Ile to the subtype B consensus Leu) partially restored infectivity for two of three chimeras tested. Similarly, mutagenesis of rev codon 78 of NL4-3 from Leu to Ile partially attenuated this virus. Ile-78 was found in all 13 clones examined from samples taken from this asymptomatic subject 4.5 years after infection, including 9 from peripheral blood mononuclear cells and 4 from a virus isolate, as well as 4 additional clones each from peripheral blood mononuclear cells sampled 37 and 51 months later. We next examined conservation of the Rev activation domain within and among long-term survivors (LTS) and patients with AIDS, as well as T-cell-line-adapted strains of HIV-1. Putative attenuating mutations were found in a minority of sequences from all five LTS and two of four patients with AIDS. Of the 11 T-cell-line-adapted viruses examined, none had these changes. Among and within LTS virus population had marginally higher levels of diversity in Rev than in Env; patients with AIDS had similar levels of diversity in the two reading frames; and T-cell-line-adapted viruses had higher levels of diversity in Env. These results are consistent with the hypothesis that asymptomatic individuals harbor attenuated variants of HIV-1 which correlate with and contribute to their lack of disease progression.

    View details for Web of Science ID A1995RN98600064

    View details for PubMedID 7637019

  • CHARACTERIZATION OF HLA-A-ASTERISK-0201-RESTRICTED CYTOTOXIC T-CELL EPITOPES IN CONSERVED REGIONS OF THE HIV TYPE-1 GP160 PROTEIN JOURNAL OF IMMUNOLOGY Dupuis, M., Kundu, S. K., Merigan, T. C. 1995; 155 (4): 2232-2239

    Abstract

    CTL activity is a major component of the host immune response associated with control of HIV replication in the course of infection. Emerging populations of HIV overcome the protective effector mechanisms with variant sequences unrecognized by CTL. Therefore, a critical element for containment of virus spread might be the establishment of an immune response against highly conserved epitopes. In this study, we selected a panel of nonamer or decamer peptides, with demonstrated binding affinity for HLA-A 0201, to define novel highly conserved envelope-derived epitopes of HIV-1. CTL activities were characterized from PBMC of five HLA-A2+, HIV-1-infected individuals given recombinant gp160. CTL activity derived from patient PBMC stimulated in vitro with peptide was demonstrated against at least two novel minimal env-encoded conserved epitopes. One epitope, KLTPLCVTL (aa 120-128), is highly conserved among HIV-1 strains of the B subtype. Analysis of a CTL clone reactivity to a distinct epitope (aa 814-823) demonstrated fluctuations in the recognition of peptides corresponding to natural virus variants found in vivo.

    View details for Web of Science ID A1995RN46400061

    View details for PubMedID 7543542

  • NEW VIROLOGICAL TOOLS FOR THE DESIGN AND ANALYSIS OF CLINICAL-TRIALS JOURNAL OF INFECTIOUS DISEASES Shafer, R. W., Merigan, T. C. 1995; 171 (5): 1325-1328

    Abstract

    While a large number of candidate drugs and drug combinations are being evaluated for treating human immunodeficiency virus (HIV) infection, clinicians are confronted by the problem of how to optimally use those antiretroviral drugs already approved for clinical use. While new techniques are being developed for studying HIV pathogenesis, clinicians are asking whether these new techniques can be used to develop improved strategies for treating the HIV-infected individual. In the current issue of the Journal, Kojima et al. from the National Cancer Institute (NCI) used two research techniques to analyze the results of a phase I/II study comparing alternating versus simultaneous therapy with zidovudine and didanosine. The authors used a quantitative polymerase chain reaction (PCR) assay for measuring plasma virus RNA and a selective PCR assay for detecting specific HIV reverse transcriptase (RT) drug-resistance mutations. Their study demonstrates the potential for effective combination therapy if drugs are optimally combined and suggests that assays for measuring HIV burden and HIV drug resistance can be used to better understand the results of preliminary clinical trials. In addition, their study raises questions about the potential role for measurements of virus burden and the detection of HIV drug resistance in larger clinical trials and clinical practice.

    View details for Web of Science ID A1995QU64000036

    View details for PubMedID 7751711

  • CLARIFICATION OF A METHOD TO REVERSE TRANSCRIBE HUMAN-IMMUNODEFICIENCY-VIRUS RNA JOURNAL OF INFECTIOUS DISEASES Kozal, M. J., Shafer, R. W., Winters, M. A., Katzenstein, D. A., Merigan, T. C. 1995; 171 (4): 1072-1072

    View details for Web of Science ID A1995QP91200060

    View details for PubMedID 7706796

  • HUMAN CYTOMEGALOVIRUS DNA IS PRESENT IN CD45(+) CELLS IN SEMEN FROM HUMAN IMMUNODEFICIENCY VIRUS-INFECTED PATIENTS JOURNAL OF INFECTIOUS DISEASES Rasmussen, L., Morris, S., Hamed, K., Merigan, T. C. 1995; 171 (2): 432-436

    Abstract

    Human cytomegalovirus (CMV) DNA was detected and quantitated in both blood and semen cells from human immunodeficiency virus (HIV)-infected men with 100-800 CD4 cell counts/mm3. None of the 35 patients studied had demonstrable CMV DNA in mononuclear cells isolated from blood. Blood samples from 8 of these patients were cultured for CMV and found to be negative. About 30% of HIV-seropositive patients in the study group had > 100 copies of CMV in semen (range, > 100 to >10(6); mean, approximately 100,000). Persistent CMV infection was detected for > 8 months in some patients with no obvious signs or symptoms of CMV disease. The CMV-infected cell in semen CD45+ and probably had Fc receptors. Mature spermatozoa were not a major reservoir of CMV infection.

    View details for Web of Science ID A1995QF22900025

    View details for PubMedID 7844383

  • Heterogeneity in long-term response to HIV-infected individuals to zidovudine and didanosine combination therapy. Journal of Infectious Diseases Merigan, T.C., Shafer R.W., Iverson A.K.N, Winters M.A., Katzenstein D.A., the ACTG 143 Virology Team. 1995: 70-78
  • AIDS 1995. Clinical treatment: overview. AIDS Weber, J., Merigan, T. C. 1995; 9: S181-2

    View details for PubMedID 8819584

  • QUANTITATIVE-ANALYSIS OF SYNCYTIUM-INDUCING AND NON-SYNCYTIUM-INDUCING VIRUS IN PATIENTS INFECTED WITH HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 JOURNAL OF CLINICAL MICROBIOLOGY Shafer, R. W., Aguiniga, E., Merigan, T. C. 1995; 33 (1): 212-214

    Abstract

    Among 75 consecutive human immunodeficiency virus type 1 (HIV-1)-infected patients with moderate and advanced immunosuppression, those harboring syncytium-inducing (SI) HIV-1 had a lower CD(4+)-cell count (145 versus 278 cells per microliter, P < 0.001) and 10-fold-higher virus titers than patients with non-SI HIV-1 (398 versus 39 infectious units per 10(6) CD4+ lymphocytes; P < 0.001). In patients with SI virus, the mean titer of SI virus, determined with a quantitative MT-2 cell assay, was 135 SI infectious units per 10(6) CD4+ lymphocytes. Virus titer correlated inversely with CD(4+)-cell count in patients with SI (r = -0.67) but not non-SI (r = -0.29) virus.

    View details for Web of Science ID A1995PX47200044

    View details for PubMedID 7699044

  • HIV virology for clinical trials. AIDS Shafer, R. W., Merigan, T. C. 1995; 9: S193-202

    View details for PubMedID 8819586

  • QUANTITATION OF HUMAN CYTOMEGALOVIRUS DNA FROM PERIPHERAL-BLOOD CELLS OF HUMAN IMMUNODEFICIENCY VIRUS-INFECTED PATIENTS COULD PREDICT CYTOMEGALOVIRUS RETINITIS JOURNAL OF INFECTIOUS DISEASES Rasmussen, L., Morris, S., Zipeto, D., Fessel, J., Wolitz, R., Dowling, A., Merigan, T. C. 1995; 171 (1): 177-182

    Abstract

    Human cytomegalovirus (CMV) DNA copy number in white blood cells from both human immunodeficiency virus (HIV)-seronegative and HIV-seropositive patients was amplified from the immediate-early region of CMV DNA and quantified by colorimetric detection of the hybridization of the amplification product to a detector oligonucleotide probe in microtiter wells. By Mann-Whitney U test, significantly higher (P < .05, two-tailed) copy numbers of CMV DNA were detected in HIV-seropositive patients with retinitis than in either patients with < 100 CD4 cells/mm3 and no symptomatic CMV disease or HIV-seropositive patients with > 100 CD4 cells/mm3. By prospective monitoring for increases in CMV DNA copy number, it may be possible to identify HIV-seropositive patients who are at imminent risk for development of symptomatic CMV retinitis.

    View details for Web of Science ID A1995PZ87300025

    View details for PubMedID 7798658

  • DETECTION OF DRUG-RESISTANCE MUTATIONS IN THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 (HIV-1) POL GENE - DIFFERENCES IN SEMEN AND BLOOD HIV-1 RNA AND PROVIRAL DNA JOURNAL OF INFECTIOUS DISEASES KROODSMA, K. L., Kozal, M. J., Hamed, K. A., Winters, M. A., Merigan, T. C. 1994; 170 (5): 1292-1295

    Abstract

    Different tissues or body fluids in which human immunodeficiency virus type 1 (HIV-1) can reside may contain viruses with distinct characteristics. Sixteen HIV-1-infected patients receiving zidovudine or didanosine were studied cross-sectionally and 1 patient who switched from zidovudine to didanosine was followed sequentially to determine if drug resistance mutations within the HIV-1 pol gene at codons 74 and 215 differed depending on the compartment from which the gene was isolated (plasma, seminal fluid, peripheral blood mononuclear cells, or seminal nonspermatozoal mononuclear cells). Cell-free virus in plasma and semen developed detectable mutations first, followed by proviral DNA in seminal nonspermatozoal and peripheral blood mononuclear cells. Study of the appearance of HIV-1 mutations in various compartments may help elucidate how the populations and dynamics of the virus differ throughout the body and determine whether seminal cell-free virus or provirus is the major sexually transmitted form.

    View details for Web of Science ID A1994PN66800038

    View details for PubMedID 7963730

  • ZIDOVUDINE AND DIDEOXYCYTIDINE DIFFER IN THEIR EFFECTS ON HUMAN IMMUNODEFICIENCY VIRUS-INDUCED PATHOLOGICAL ACTIVATION OF THE IMMUNE-SYSTEM JOURNAL OF INFECTIOUS DISEASES Liu, M., FAHEY, J. L., Aziz, N., Cumberland, W. G., Skowron, G., Merigan, T. 1994; 170 (5): 1165-1171

    Abstract

    When zidovudine and dideoxycytidine (ddC) were given on schedules of 1 week on drug and 1 week off, results differed substantially in effects on HIV (human immunodeficiency virus type 1)-induced immune activation. Zidovudine (200 mg every 4 h) caused marked lowering toward normal of serum neopterin and beta 2-microglobulin within 1 week. This effect was lost within 1 week off zidovudine. Intermittent ddC (0.03 mg/kg every 4 h) had a smaller 1-week effect but had a delayed cumulative suppressive effect on HIV-associated immune activation that was not seen with intermittent zidovudine therapy. Zidovudine and ddC given in alternating weeks had synergistic effects in the first 10 weeks (e.g., early and rapid reduction followed by cumulatively greater effects on immune cell activation). The identical sawtooth effect of intermittent zidovudine was also evident in serum HIV p24 antigen levels. This is consistent with the hypothesis that the increased serum levels of the immune activation markers seen in HIV infection reflect stimulatory effects of HIV viral components on immune system cells.

    View details for Web of Science ID A1994PN66800017

    View details for PubMedID 7963709

  • LONG-TERM EFFECTS OF INTERLEUKIN-2 ON CD4 CELL COUNTS IN HUMAN IMMUNODEFICIENCY VIRUS-INFECTED PATIENTS JOURNAL OF INFECTIOUS DISEASES Ramachandran, R. V., KATZENSTEIN, D., Merigan, T. C. 1994; 170 (4): 1044-1046

    View details for Web of Science ID A1994PJ69400052

    View details for PubMedID 7930706

  • FAILURE OF SHORT-TERM CD4-PE40 INFUSIONS TO REDUCE VIRUS LOAD IN HUMAN IMMUNODEFICIENCY VIRUS-INFECTED PERSONS JOURNAL OF INFECTIOUS DISEASES Ramachandran, R. V., Katzenstein, D. A., Wood, R., Batts, D. H., Merigan, T. C. 1994; 170 (4): 1009-1013

    Abstract

    The safety, immunologic, and antiviral effects of a recombinant biologic product that combines the second and third domains of the CD4 molecule and Pseudomonas exotoxin A (PE40) were evaluated in 21 human immunodeficiency virus (HIV)-infected subjects in a phase III open-label dose-ranging study. Subjects with CD4+ lymphocyte counts of 100-500/mm3 received CD4-PE40 at 40, 80, or 160 micrograms/m2 by infusion three to seven times over 10 days. At the maximum tolerated dose (80 micrograms/m2), peak CD4-PE40 levels were 65-130 ng/mL with a serum half-life of 3.6 +/- 1.5 h. Toxicity, primarily increased hepatic transaminases, was dose-related and reversible. HIV DNA proviral levels in peripheral blood mononuclear cells and plasma HIV RNA remained stable during and after CD4-PE40 infusions. The relative resistance of clinical isolates of HIV, limits of the tolerated dose, and the immunogenicity and short half-life of the protein may explain the lack of in vivo antiviral effect of CD4-PE40.

    View details for Web of Science ID A1994PJ69400041

    View details for PubMedID 7930696

  • RELATIONSHIP OF HIV-1 PROVIRUS LOAD, CD8+ CD11+ T-CELLS AND HIV-1 ENVELOPE-SPECIFIC CYTOTOXIC T-LYMPHOCYTES IN HIV-INFECTED ASYMPTOMATIC PATIENTS IMMUNOLOGY Kundu, S. K., Merigan, T. C. 1994; 83 (1): 81-85

    Abstract

    The course of human immunodeficiency virus (HIV) infection progresses from an acute infection, through a prolonged asymptomatic phase, to an immunocompromised state. Some of the possible mechanisms underlying immune dysfunction include decreased HIV-specific cytotoxic T lymphocyte (CTL) activity, increased suppressor T cells, and/or increased HIV load. However, no study has been carried out to correlate all these factors. In this study, 26 patients showed > 3 log DNA copy number/10(6) CD4+ T cells, and seven patients had < 3 log DNA copy/10(6) CD4+ T cells. Patients with higher virus load had greater than 15% (19-45%) CD8+ CD11+ T cells. HIV-1 envelope-specific, HLA-restricted CTL activity (> 10%) was observed in 11 of 25 asymptomatic patients, and the remaining 14 patients lacked CTL activity (< 10%) in bulk assay. Although CTL activity was undetectable in these individuals, there was no significant difference in the frequency of activated CTL and their precursors in limiting dilution analysis. The patients with undetectable CTL activity had a higher percentage of CD8+ CD11+ T cells and a higher HIV-1 DNA copy number/million CD4+ T cells. Each of these parameters were significantly correlated with CD4+ T-cell numbers. The inverse relationship of CD8+ CD11+ T cells and virus load with HIV-specific CTL activity observed in this study may be one of the underlying factors which determines the course of HIV infection.

    View details for Web of Science ID A1994PF60400013

    View details for PubMedID 7821971

  • DEFICIENCY IN ANTIBODY-RESPONSE TO HUMAN CYTOMEGALOVIRUS GLYCOPROTEIN GH IN HUMAN IMMUNODEFICIENCY VIRUS-TREATED PATIENTS AT RISK FOR CYTOMEGALOVIRUS RETINITIS JOURNAL OF INFECTIOUS DISEASES Rasmussen, L., Morris, S., Wolitz, R., Dowling, A., Fessell, J., Holodniy, M., Merigan, T. C. 1994; 170 (3): 673-677

    Abstract

    Human immunodeficiency virus (HIV)-infected patients at risk for symptomatic human cytomegalovirus (CMV) infection were studied for serum antibody to CMV glycoproteins gH and gB. Antibody titers to gB in HIV-seropositive patients, irrespective of CD4 cell counts or presence of CMV retinitis, were significantly higher than titers in HIV-seronegative, CMV-seropositive patients but were comparable to titers detected in HIV-seronegative patients with CMV mononucleosis. In contrast, antibody to gH was rarely detected in HIV-seropositive patients with CD4 cell counts > 100/mm3 compared with patients with counts > 100/mm3. The inability to detect gH antibody at a time of high risk for symptomatic CMV retinitis suggests that immune intervention with either gH-specific vaccine or passive immunotherapy may benefit HIV-infected persons at risk for symptomatic CMV disease.

    View details for Web of Science ID A1994PE26500026

    View details for PubMedID 7915750

  • DIDANOSINE RESISTANCE IN HIV-INFECTED PATIENTS SWITCHED FROM ZIDOVUDINE TO DIDANOSINE MONOTHERAPY ANNALS OF INTERNAL MEDICINE Kozal, M. J., Kroodsma, K., Winters, M. A., Shafer, R. W., Efron, B., Katzenstein, D. A., Merigan, T. C. 1994; 121 (4): 263-268

    Abstract

    To determine the frequency and pattern of development of specific drug resistance mutations for human immunodeficiency virus (HIV) reverse transcriptase in patients switched from zidovudine to didanosine therapy and to examine the relation of the didanosine resistance mutation at codon 74 of the HIV reverse-transcriptase gene to CD4+ T-cell changes and virus burden.Retrospective analysis of all patients enrolled at Stanford University in protocols where patients were switched from zidovudine to didanosine monotherapy.A university hospital.64 patients infected with HIV who were switched from zidovudine to didanosine monotherapy. Patients had the acquired immunodeficiency syndrome (AIDS), AIDS-related complex, or were asymptomatic (mean [+/- SD] starting CD4+ T-cell count of 129 +/- 88 cells/mm3).Serial serum specimens were tested for the didanosine resistance mutation at codon 74 of the HIV reverse-transcriptase gene and for a zidovudine resistance mutation at codon 215 using selective polymerase chain reactions (PCR). Serum HIV RNA levels were determined by quantitative PCR. CD4+ T-cell counts were determined at serial time points.By 24 weeks of didanosine therapy, the proportion of patients with the didanosine resistance mutation at codon 74 increased from 0% to 56% (36 of 64). In contrast, the proportion of patients with the zidovudine resistance mutation at codon 215 decreased from 84% at the start to 59% after 24 weeks of didanosine therapy (a 25% decrease, 95% lower CI, 15%; P < 0.0001). Patients who developed the codon 74 mutation had a greater decrease in CD4+ T cells after the development of the mutation than did patients without the mutation (P < 0.001). In addition, after 24 weeks of didanosine, patients who developed the codon 74 mutation had a greater serum HIV RNA burden than patients who remained wild type (did not have the mutation) at codon 74 (225,000 compared with 82,400 HIV RNA copies/mL serum; P = 0.01).Among patients infected with HIV who had advanced disease and were switched from zidovudine to didanosine therapy, more than one half developed the didanosine resistance mutation at codon 74 by 24 weeks of didanosine therapy. Patients who developed the codon 74 mutation had a greater decline in CD4+ T cells after the development of the mutation and had a greater serum virus burden than did patients without the codon 74 mutation.

    View details for Web of Science ID A1994PB10200005

    View details for PubMedID 7518658

  • HIV-1 SYNCYTIUM-INDUCING PHENOTYPE, VIRUS BURDEN CODON-215 REVERSE-TRANSCRIPTASE MUTATION AND CD4 CELL DECLINE IN ZIDOVUDINE-TREATED PATIENTS JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY Kozal, M. J., Shafer, R. W., Winters, M. A., Katzenstein, D. A., Aguiniga, E., Halpern, J., Merigan, T. C. 1994; 7 (8): 832-838

    Abstract

    The variable rate of disease progression in HIV-1-infected patients treated with zidovudine may be related to certain viral characteristics, such as, antiviral drug resistance, virus burden, and viral syncytium-inducing (SI) capacity. Thirty-two HIV-1-infected patients treated with zidovudine (mean of 34 months) were studied to determine the relationship of SI phenotype and the codon 215 pol gene mutation (a marker of zidovudine resistance) to virus burden and CD4 cell decline. Patients with SI strains and the codon 215 mutation in their proviral DNA had a 54% decline in CD4 cells and a virus burden of 21,480 proviral DNA copies/10(6) CD4 cells. In contrast, patients with non-SI (NSI) strains and wild-type at codon 215 had a 10% increase in CD4 cells and had a viral burden 1/46 that of patients with SI and the 215 mutation. Among patients with NSI strains, changes in CD4 cells depended on the presence of the codon 215 mutation (-160 CD4 cells/microliters), compared with those wild-type at codon 215 (+28 CD4 cells/microliters) (p < 0.01). There was a concordant rise in virus burden between proviral DNA and plasma HIV RNA depending on HIV phenotype and genotype. Using multiple linear regression, SI phenotype and the codon 215 mutation were found to independently predict CD4 cell decline and increased virus burden in zidovudine-treated patients.

    View details for Web of Science ID A1994NX17100007

    View details for PubMedID 7517448

  • DIURNAL AND SHORT-TERM STABILITY OF HIV VIRUS LOAD AS MEASURED BY GENE AMPLIFICATION JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Holodniy, M., Mole, L., Winters, M., Merigan, T. C. 1994; 7 (4): 363-368

    Abstract

    To determine whether human immunodeficiency virus (HIV) viral load has short term stability, eight clinically stable subjects infected with HIV and having CD4 counts ranging between 10-600/mm3, had blood samples taken at 0800 and 1700 on 3 consecutive days and then weekly at 0800 for 1 month (8-10 observations/subject). Plasma HIV RNA, peripheral blood mononuclear cell (PBMC) proviral DNA, serum p24 antigen levels, and mononuclear cell subsets were measured at each time point. Mean plasma HIV RNA, PBMC HIV DNA, and p24 antigen [both regular and immune complex dissociated (ICD)] levels did not change significantly between mornings and afternoons or on successive days or weeks. CD4+, CD8+, and CD56+ number demonstrated a diurnal variation in those subjects with > 200 CD4 cells/mm3. We conclude that HIV viral load demonstrates short-term stability in clinically stable subjects. This stability has important implications for monitoring HIV disease progression or antiretroviral therapy.

    View details for Web of Science ID A1994NC77500007

    View details for PubMedID 7907661

  • DISPOSITION OF ANTIGEN-PRESENTING LIPOSOMES IN-VIVO - EFFECT ON PRESENTATION OF HERPES-SIMPLEX VIRUS-ANTIGEN RGD VACCINE Ho, R. J., BURKE, R. L., Merigan, T. C. 1994; 12 (3): 235-242

    Abstract

    Antigen-presenting liposomes (APLs) containing a lipophilic derivative of muramyl tripeptide (MTP-PE) have previously been shown to enhance the immunotherapeutic effects mediated by HSV recombinant protein gD (rgD) after HSV type 2 infection is established. In this study, both the in vivo disposition of rgD and the immunological activity of in vivo-delivered rgD were determined. Following intravenous administration, most of the liposome-encapsulated rgD accumulated rapidly, mainly in the spleen, while most of the soluble rgD was quickly eliminated through the kidney. We have compared the T-cell stimulatory effects of macrophages, B cells and dendritic cells from the spleens of animals treated with rgD in vivo. Of these antigen-presenting cells, only adherent macrophages, isolated from the spleens of animals treated with rgD encapsulated in APLs for 90 minutes, were capable of stimulating HSV-sensitized autologous T and B cells. Additional in vitro exposure of macrophages to rgD was not required. In contrast, spleen macrophages from HSV-sensitized animals exposed to either empty liposomes or free rgD did not exhibit such immune responses, indicating that the immunobiological effect of the rgD delivered in APLs is antigen- and carrier-specific. The enhanced delivery of antigen to spleen cells, coupled with MTP-PE immunostimulatory activity, may be the key factors for the enhanced therapeutic effects observed in treating HSV-2 disease in guinea pigs. This approach will be useful to enhance the induction of secondary immune responses in postinfection vaccination schemes.

    View details for Web of Science ID A1994MU36900007

    View details for PubMedID 8165856

  • QUANTITATION OF HUMAN-IMMUNODEFICIENCY-VIRUS BY CULTURE AND POLYMERASE CHAIN-REACTION IN RESPONSE TO DIDANOSINE AFTER LONG-TERM THERAPY WITH ZIDOVUDINE JOURNAL OF INFECTIOUS DISEASES Katzenstein, D. A., Winters, M., BUBP, J., Israelski, D., Winger, E., Merigan, T. C. 1994; 169 (2): 416-419

    Abstract

    Measurements of human immunodeficiency virus by quantitative RNA and DNA polymerase chain reaction (PCR), cell and plasma infectivity dilution cultures, and immune complex-disassociated p24 antigen-capture ELISA were made repeatedly in 10 subjects receiving long-term zidovudine treatment before and after therapy was changed to didanosine. Comparison of baseline assays showed that quantitative cell cultures, plasma RNA, and proviral DNA were measurable in all subjects and that cell culture results were significantly correlated with measures of nucleic acids. Plasma viremia (as indicated by culture) and p24 antigen were detected in three measurements in 3 of 8 and 6 of 10 subjects, respectively. Significant decreases in plasma RNA and cell dilution cultures from baseline were maintained for up to 6 months after initiation of didanosine therapy. These findings demonstrate a decrease in virus burden with the use of didanosine; however, continued detection of plasma RNA suggests that additional antiviral therapy will be required to suppress viral replication.

    View details for Web of Science ID A1994MV82900028

    View details for PubMedID 7906292

  • HUMAN-IMMUNODEFICIENCY-VIRUS ENVELOPE GLYCOPROTEINS JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY Merigan, T. C., Kundu, S. K. 1994; 7: S14-S20

    Abstract

    Given the long-term clinical latency and high level of replication of human immunodeficiency virus (HIV), it is not surprising that HIV has developed a method of persistence involving production of novel variants in its proteins. Therapeutic vaccines attempt to harness enhanced immune mechanisms to control viral replication, and thus prevent disease progression. A major problem in the development of a vaccine is the great variety of viral quasispecies in HIV infection worldwide and within the lifetime of a given individual. Furthermore, the protective immune parameters that correlate with the ability to control disease progression remain undefined. Manufacturers have followed a number of paths to select an immunogen. At present, investigators are monitoring different immune and viral parameters to measure the effects of therapeutic vaccination. This monitoring ranges from HIV-specific cellular and humoral immunity to viral load markers and skin tests to recall antigens. Two possible major limitations to this treatment approach are the declining potency of the immune response and the ability of the virus to produce escape mutants, particularly during disease progression as viral replication increases. The latter escape mechanism could be similar to the specific pol mutations that enable the virus to escape the impact of drug therapy. Although apparent safety has been observed in phase II/III studies using several HIV envelope-based therapeutic vaccines, investigators have documented reproducible immunogenicity only in HIV-seropositive individuals with CD4+ T cells > 400/mm3. A convincing impact of vaccine therapy on viral load or the course of HIV disease has not been demonstrated.

    View details for Web of Science ID A1994NP87200004

    View details for PubMedID 8182509

  • BIOLOGICAL VARIATION AND QUALITY-CONTROL OF PLASMA HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 RNA QUANTITATION BY REVERSE-TRANSCRIPTASE POLYMERASE CHAIN-REACTION JOURNAL OF CLINICAL MICROBIOLOGY Winters, M. A., Tan, L. B., Katzenstein, D. A., Merigan, T. C. 1993; 31 (11): 2960-2966

    Abstract

    Quantitation of human immunodeficiency virus type 1 (HIV-1) RNA in the plasma of seropositive individuals was performed by using an external control assay with techniques to standardize and control each measurement. Rigorous study of the variability of the assay showed that the median intraassay reproducibility was log10 0.15 RNA copies per ml of plasma, while the median interassay reproducibility on replicate plasma samples was log10 0.25 copies perml. Specimen stability studies showed reproducible recovery of RNA from plasma stored at -70 degrees C for up to 12 months. In clinically stable patients who were either untreated or taking zidovudine, the average week-to-week variation in plasma RNA levels, measured in real time, was log10 0.30 RNA copies per ml. In contrast, patients either initiating or changing antiretroviral therapy showed a fall of log10 0.8 to log10 2.0 copies per ml in plasma RNA levels. Overall, 105 of 110 (96%) HIV-1-seropositive individuals with CD4 counts of 36 to 868 cells per mm3 had quantifiable HIV-1 RNA over a range of log10 2.70 to log10 6.23 RNA copies per ml, including 81% (13 of 16) of the individuals with greater than 500 CD4 cells per mm3. Accurate and reproducible quantitation of plasma viremia in real time by reverse transcriptase polymerase chain reaction, particularly in asymptomatic HIV-1-infected individuals with high CD4 counts, provides a basis for the use of this virologic measure to monitor the short- and long-term effects of early intervention therapeutic strategies on viral burden.

    View details for Web of Science ID A1993MC28900022

    View details for PubMedID 7903317

  • CONTINUOUS PRESENCE OF CD4-PE40 IS REQUIRED FOR ANTIVIRAL ACTIVITY AGAINST SINGLE-PASSAGE HIV ISOLATES AND INFECTED PERIPHERAL-BLOOD MONONUCLEAR-CELLS AIDS RESEARCH AND HUMAN RETROVIRUSES Winters, M. A., Merigan, T. C. 1993; 9 (11): 1091-1096

    Abstract

    CD4-PE40, a recombinant protein consisting of a portion of human CD4 linked to Pseudomonas aeruginosa exotoxin, was studied in vitro to assess its ability to inhibit the replication of primary isolates of HIV. CD4-PE40 was added to cultures of phytohemagglutin (PHA)-stimulated normal peripheral blood mononuclear cells (PBMCs) infected either with the laboratory strain HIVIIIb or single-passage virus stocks derived from patient PBMCs. Results showed that the replication of HIVIIIb was inhibited by a single pulse of CD4-PE40 and, more significantly, by continuous exposure to the drug. The replication of primary virus isolates, however, was inhibited only by continuous exposure to CD4-PE40. Cultures of freshly isolated PBMCs from HIV-seropositive individuals that were directly treated with CD4-PE40 before culture also required the continuous presence of drug to demonstrate inhibition of HIV replication. These results suggest that continuous administration of CD4-PE40 may be required to produce a significant anti-HIV effect in vivo.

    View details for Web of Science ID A1993MK13000007

    View details for PubMedID 8312052

  • PERIPHERAL-BLOOD MONONUCLEAR CELL HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 PROVIRAL DNA QUANTIFICATION BY POLYMERASE CHAIN-REACTION - RELATIONSHIP TO IMMUNODEFICIENCY AND DRUG EFFECT JOURNAL OF CLINICAL MICROBIOLOGY Montoya, J. G., Wood, R., KATZENSTEIN, D., HOLODNY, M., Merigan, T. C. 1993; 31 (10): 2692-2696

    Abstract

    Human immunodeficiency virus type 1 (HIV-1) proviral DNA from peripheral blood mononuclear cells (PBMCs) was quantitated in 61 HIV-1-seropositive individuals by a nonisotopic polymerase chain reaction assay. Primers from the gag region (SK38, SK39) were used to determine the log10 HIV-1 proviral copy number per 10(6) CD4+ T lymphocytes (peripheral blood proviral load). A standard curve was generated for each assay by using ACH-2 cell DNA. The peripheral blood proviral load was followed in 15 individuals in a longitudinal study and was measured in 45 individuals in a cross-sectional analysis. Three of four untreated patients who were followed for 14 months had stable PBMC proviral loads and CD4+ T lymphocyte counts; one untreated patient had a sustained increase in PBMC proviral load followed 5 months later by a significant decline in the CD4+ T lymphocyte count. Eleven previously untreated individuals were monitored for 1 year following initiation of zidovudine and/or 2',3'-dideoxyinosine therapy. The mean log10 number of proviral HIV-1 copies per 10(6) CD4+ T cells decreased from 4.3 +/- 0.4 at the baseline to 3.5 +/- 0.6 after 2 to 4 months of therapy (P < 0.01). This initial 0.8 log10 fall in the PBMC proviral load after the initiation of therapy was followed by a rise in the PBMC proviral load by the sixth month of therapy. The PBMC proviral load in 45 subjects, both treated (n = 25) and untreated (n = 20), correlated inversely with the CD4+ T lymphocyte count (P < 0.01, R = 0.49). PBMC proviral DNA quantification by a nonisotopic polymerase chain reaction assay correlates with HIV-1 disease progression and could be used to monitor the effect of antiretroviral therapy.

    View details for Web of Science ID A1993LY05900024

    View details for PubMedID 7902845

  • DETECTION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 IN SEMEN - EFFECTS OF DISEASE STAGE AND NUCLEOSIDE THERAPY JOURNAL OF INFECTIOUS DISEASES Hamed, K. A., Winters, M. A., Holodniy, M., Katzenstein, D. A., Merigan, T. C. 1993; 167 (4): 798-802

    Abstract

    The effects of clinical stage of infection and antiviral therapy on the detection of human immunodeficiency virus type 1 (HIV-1) nucleic acids in semen were investigated by the polymerase chain reaction. HIV-1 was detected in 45 (87%) of 52 semen specimens from 29 (81%) of 36 men. Seventeen (77%) of 22 stage II or III subjects and 12 (86%) of 14 stage IV subjects had positive specimens. The CD4+ lymphocyte count was not significantly different comparing subjects with positive and negative semen. Moreover, 6 (67%) of 9 untreated men had positive specimens compared with 23 (85%) of 27 men treated with zidovudine, 2',3'-dideoxyinosine, or both for a mean of 20 months. Thus, the detection of HIV-1 in semen was independent of both stage of infection and long-term treatment. In a semiquantitative analysis of 6 men followed for 8 weeks after the start of nucleoside therapy, a decrease in HIV-1 RNA in seminal plasma was demonstrated in 2.

    View details for Web of Science ID A1993KU08600002

    View details for PubMedID 8450243

  • MEASUREMENT OF HIV VIRUS LOAD AND GENOTYPIC RESISTANCE BY GENE AMPLIFICATION IN ASYMPTOMATIC SUBJECTS TREATED WITH COMBINATION THERAPY JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Holodniy, M., KATZENSTEIN, D., Winters, M., Montoya, J., Shafer, R., Kozal, M., Ragni, M., Merigan, T. C. 1993; 6 (4): 366-369

    Abstract

    Quantification of viral load in HIV disease has become increasingly important as a marker of antiviral efficacy. We applied gene amplification techniques in vivo to asses antiretroviral activity of combination therapy. Five HIV-infected subjects, four of whom were drug naive, were administered combination therapy with zidovudine (ZDV) and didanosine (ddI). Plasma and peripheral blood mononuclear cells (PBMC) were obtained twice at baseline and then at 1, 3, 6, 9, and 12 months after the initiation of therapy. Results show that plasma HIV RNA copy number fell from 2,170 +/- 660/ml to undetectable at 1 month, with continued suppression at 12 months. HIV proviral DNA copy number decreased from 3.9 to 3.0 log10/10(6) CD4+ T cells at 12 months. Cell dilution cultures were positive in 4 of 5 subjects at baseline and in only 1 of 5 after 12 months. CD4+ T-cell count increased from 390 +/- 30/mm3 pretherapy, to 505 +/- 66/mm3 after 6 months of therapy, but returned to baseline levels after 12 months of therapy. No mutations were detected from PBMC DNA for codon 215 and 74 in the HIV pol gene from the drug-naive subjects. These findings suggest that gene amplification techniques can be used to study changes in viral load or genotype and can be applied in real time to samples from patients involved in clinical trials.

    View details for Web of Science ID A1993KU22100007

    View details for PubMedID 8095981

  • ZIDOVUDINE SUSCEPTIBILITY TESTING OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 (HIV) CLINICAL ISOLATES JOURNAL OF VIROLOGICAL METHODS Shafer, R. W., Kozal, M. J., Katzenstein, D. A., LIPIL, W. H., JOHNSTONE, I. F., Merigan, T. C. 1993; 41 (3): 297-310

    Abstract

    Traditional antiviral susceptibility testing methods using cell lines can be applied to no more than about 30% of clinical HIV isolates (Larder et al., 1989a; Fenyo et al., 1989). We tested the cell-free supernatant from low passage clinical HIV isolates using donor peripheral blood mononuclear cells (PBMC). Drug susceptibility was assessed by measuring the effect of increasing zidovudine (ZDV) concentrations on HIV P24 antigen production. Susceptibility results were obtained on 24/27 consecutive clinical isolates and 6/6 laboratory isolates. The mean IC90 of isolates from untreated patients was 0.008 microM ZDV (range: 0.002-0.038). The IC90s of isolates from ZDV-treated patients ranged from 0.007 to greater than 10 microM ZDV. All isolates with an IC90 < 0.1 microM ZDV had a wild type sequence at codon 215 of the HIV pol gene; 11/12 isolates with an IC90 > 0.1 microM ZDV had a mutation at codon 215 (P < 0.001). Among 16 ZDV-treated patients, there was a modest correlation between the change in CD4 count from the start of ZDV treatment and the IC90 of the patient's isolate following treatment (r = 0.51). Susceptibility testing using donor PBMC can be a sensitive means of testing a broad range of clinical HIV isolates.

    View details for Web of Science ID A1993KR99500004

    View details for PubMedID 8097199

  • A MUTATION IN HUMAN-IMMUNODEFICIENCY-VIRUS REVERSE-TRANSCRIPTASE AND DECLINE IN LYMPHOCYTE-CD4 NUMBERS IN LONG-TERM ZIDOVUDINE RECIPIENTS JOURNAL OF INFECTIOUS DISEASES Kozal, M. J., Shafer, R. W., Winters, M. A., Katzenstein, D. A., Merigan, T. C. 1993; 167 (3): 526-532

    Abstract

    A nested polymerase chain reaction assay was used to define the sequence of a specific codon, amino acid 215, of the human immunodeficiency virus (HIV) pol gene in DNA from peripheral blood mononuclear cells (PBMC) and viral RNA from serum from 38 patients treated with zidovudine for > or = 2 years. After treatment for a mean of 34 months, 17 patients with sequences with a codon 215 mutation had a mean 50% decrease in CD4 cells, compared with 21 patients with sequences wild-type at codon 215, who had a mean 11% increase in CD4 cells (P < .0001). Patients with a mutation at 215 had a ninefold higher provirus burden in PBMC. Detection of the codon 215 mutation in plasma viral RNA preceded detection of the mutation in DNA from PBMC and decline in CD4 cells. The appearance of a mutation at codon 215 in the HIV reverse transcriptase gene in patients receiving zidovudine may be a marker for impending immunologic decline.

    View details for Web of Science ID A1993KN15200002

    View details for PubMedID 7680058

  • QUANTIFICATION AND COMPARISON OF HIV-1 PROVIRAL LOAD IN PERIPHERAL-BLOOD MONONUCLEAR-CELLS AND ISOLATED CD4+ T-CELLS JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Wood, R., Dong, H. L., Katzenstein, D. A., Merigan, T. C. 1993; 6 (3): 237-240

    Abstract

    HIV proviral load was determined by quantitative DNA polymerase chain reaction (PCR) in peripheral blood mononuclear cells (PBMC) and lymphocyte subsets isolated by cell sorter. Provirus measured in PBMC, when expressed as HIV copy number per million CD4+ cells, resulted in values which approximated those obtained from sorted CD4+ T lymphocytes. A cross sectional analysis of HIV proviral load in CD4+ T cells from 25 previously untreated and 30 zidovudine-treated seropositive patients with CD4+ T-cell counts between 25 and 802/mm3 demonstrated HIV copy numbers ranging from 1 copy per 10,000 cells in early disease to 1 copy per 10 cells in advanced disease. HIV proviral load can be rapidly assayed by PCR to give a reproducible value which varies over a 1,000-fold range and is positively correlated with cell infectivity as measured by a quantitative micrococulture assay. A less technically demanding assay using PBMC as substrate can give similar results to those obtained with sorted CD4+ T cells.

    View details for Web of Science ID A1993KN54200004

    View details for PubMedID 8450397

  • ALTERNATING AND INTERMITTENT REGIMENS OF ZIDOVUDINE AND DIDEOXYCYTIDINE IN PATIENTS WITH AIDS OR AIDS-RELATED COMPLEX ANNALS OF INTERNAL MEDICINE Skowron, G., Bozzette, S. A., Lim, L., Pettinelli, C. B., Schaumburg, H. H., Arezzo, J., Fischl, M. A., Powderly, W. G., GOCKE, D. J., Richman, D. D., Pottage, J. C., ANTONISKIS, D., McKinley, G. F., Hyslop, N. E., Ray, G., Simon, G., Reed, N., LOFARO, M. L., Uttamchandani, R. B., Gelb, L. D., Sperber, S. J., Murphy, R. L., Leedom, J. M., Grieco, M. H., Zachary, J., Hirsch, M. S., Spector, S. A., Bigley, J., SOO, W. J., Merigan, T. C. 1993; 118 (5): 321-330

    Abstract

    To determine whether alternating regimens consisting of zidovudine and 2',3'-dideoxycytidine (ddC) reduce the toxicity and maintain or increase the antiretroviral effect associated with each drug alone.An unblinded, randomized (phase II) clinical trial in which seven treatment regimens were compared.Outpatient clinics of 12 AIDS Clinical Trials Units.One hundred thirty-one patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex and serum p24 antigenemia (> or = 70 pg/mL).Treatments included weekly or monthly alternating zidovudine (200 mg every 4 hours) and ddC (0.01 or 0.03 mg/kg body weight every 4 hours); weekly intermittent zidovudine, 200 mg every 4 hours, or ddC, 0.03 mg/kg every 4 hours; and continuous zidovudine.Toxicity, CD4 cell counts, serum p24 antigen levels, and clinical end points. Data were analyzed for the first 48 weeks of therapy (median follow-up, 40 weeks).Hematologic toxicity was significantly less frequent in patients who received zidovudine therapy every other week (11% to 15%) or every other month (11% to 14%) than in those who received continuous zidovudine therapy (33%) (P < 0.02). Weekly alternating therapy with zidovudine and ddC, 0.03 mg/kg, or intermittent therapy with ddC, 0.03 mg/kg, produced high rates of peripheral neuropathy (41% and 50%, respectively). Neuropathy occurred in 10% to 21% of patients in the other three alternating-therapy limbs and in 17% of patients receiving zidovudine alone (intermittently or continuously). Initial increases in CD4 cell counts were sustained in three alternating-therapy limbs, but counts returned to baseline by week 28 in the remaining limbs. The median weight gain at week 48 was significantly greater in patients treated with alternating regimens (0.9 to 3.8 kg) compared with those treated with continuous zidovudine therapy (-0.7 kg) (P = 0.008). Patients treated with alternating regimens and those treated with continuous zidovudine had similarly sustained decreases in p24 antigen levels.These findings suggest that alternating therapy with zidovudine and ddC reduces the toxicity associated with each drug alone while maintaining strong antiretroviral activity.

    View details for Web of Science ID A1993KN68800001

    View details for PubMedID 8094279

  • SAFETY AND EFFICACY OF POLYETHYLENE-GLYCOL MODIFIED INTERLEUKIN-2 AND ZIDOVUDINE IN HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 INFECTION - A PHASE I-II STUDY JOURNAL OF INFECTIOUS DISEASES Wood, R., Montoya, J. G., Kundu, S. K., Schwartz, D. H., Merigan, T. C. 1993; 167 (3): 519-525

    Abstract

    The safety and efficacy of combined therapy with polyethylene glycolated (PEG) interleukin (IL)-2 and zidovudine was assessed in 19 human immunodeficiency virus type 1 (HIV-1)-seropositive subjects in a phase I/II open-label dose-ranging study. During courses of three weekly infusions of PEG IL-2, dose-limiting side effects were seen at 5 x 10(6) IU/m2 and reversible encephalopathy in 1 subject at 3 x 10(6) IU/m2. Significant increases were seen in CD4 cell counts (P < .01), NK cell activity (P < .05), and HIV-specific cytotoxicity (P < .01). Virologic monitoring (quantitative DNA polymerase chain reaction and p24 antigen assay) showed no evidence of increased HIV activation. Patients with CD4 cells < 200/mm3 were entered into a chronic dosing phase. PEG IL-2 was given at 14-day intervals at doses of 10(6) IU/m2 for 8 weeks and 3 x 10(6) IU/m2 for up to 16 weeks, resulting in mean CD4 cell count elevations of 16% and 33%, respectively. PEG IL-2 appears to warrant further investigation, especially in subjects with CD4 cell counts < 200/mm3, to determine whether increased lymphocyte numbers will translate into improved clinical outcome.

    View details for Web of Science ID A1993KN15200001

    View details for PubMedID 8095058

  • 2',3'-DIDEOXYCYTIDINE (DDC) TOXIC NEUROPATHY - A STUDY OF 52 PATIENTS NEUROLOGY Berger, A. R., Arezzo, J. C., Schaumburg, H. H., Skowron, G., Merigan, T., Bozzette, S., Richman, D., SOO, W. 1993; 43 (2): 358-362

    Abstract

    We administered the antiviral agent 2',3'-dideoxycytidine (ddC) to HIV-infected patients with either ARC or AIDS as part of the AIDS Clinical Treatment Group protocol 012 and serially evaluated them with neuropathic symptom questionnaires, neurologic examinations, nerve conduction studies, and quantitative sensory testing (QST). All patients treated with high-dose ddC (0.06 and 0.03 mg/kg every 4 hours) developed a painful, predominantly sensory peripheral neuropathy, with a mean onset of 7.7 weeks, which reached severe intensity over several days. Abnormalities of vibration QST threshold preceded clinical symptoms. Treatment with 0.01 mg/kg every 4 hours produced a similar neuropathy, although of milder severity, later onset (mean, 9.3 weeks), and slower progression. In these patients, the onset of clinical symptoms and QST abnormalities were coincident. Only two of six patients treated with 0.005 mg/kg every 4 hours developed clinical or laboratory evidence of neuropathy; in both cases it was very mild and delayed in onset (26 weeks). All patients treated with high-dose ddC reported progression of symptoms (coasting) for 2 to 3 weeks following discontinuation of therapy. This study documents a painful sensory neuropathy resulting from treatment with ddC. With high-dose treatment, only the rapidity of onset and progression differentiated it from the distal, predominantly sensory neuropathy of AIDS.

    View details for Web of Science ID A1993KM76800020

    View details for PubMedID 8382349

  • PHARMACOKINETICS OF ZIDOVUDINE ALONE AND IN COMBINATION WITH OXAZEPAM IN THE HIV INFECTED PATIENT JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY Mole, L., Israelski, D., BUBP, J., OHANLEY, P., Merigan, T., Blaschke, T. 1993; 6 (1): 56-60

    Abstract

    This three-phase study was designed to determine if a pharmacokinetic drug-drug interaction exists between zidovudine and oxazepam. Six individuals infected with human immunodeficiency virus (HIV) and receiving zidovudine at 500 mg daily, with normal renal and hepatic function, were enrolled. During phase I, zidovudine pharmacokinetics were studied after steady-state oral administration (100 mg every 4 h) and after a single dose (70 mg) of intravenous zidovudine. Phase II consisted of a single oral dose (30 mg) of oxazepam followed by a 48-h blood sampling period. Phase III began with 48 h of concomitant zidovudine, 100 mg orally every 4 h, and oxazepam, 15 mg orally every 8 h, followed by concomitant dosing of intravenous zidovudine and oral oxazepam. Zidovudine concentrations were determined by radioimmunoassay. Oxazepam concentrations were determined with use of a fluorescence polarization immunoassay. The calculated bioavailability was 0.61 for zidovudine alone and 0.75 when administered in combination with oxazepam (p = 0.16). Plasma half-life for oral zidovudine alone and in combination with oxazepam was 1.17 h versus 0.99 h, respectively (p = 0.25), and 1.38 h versus 1.15 h (p = 0.38) for intravenous zidovudine during single and combination therapy, respectively. Total body clearance of zidovudine was not significantly altered by oxazepam (93 L/h vs. 109 L/h, p = 0.16). The mean pharmacokinetic parameters determined for a single 30-mg dose of oxazepam for oral clearance, apparent volume of distribution, and plasma half-life were 9.8 L/h, 65.7 L, and 5.1 h, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1993KE09500008

    View details for PubMedID 8417175

  • ENHANCEMENT OF HUMAN-IMMUNODEFICIENCY-VIRUS (HIV)-SPECIFIC CD4+ AND CD8+ CYTOTOXIC LYMPHOCYTE-T ACTIVITIES IN HIV-INFECTED ASYMPTOMATIC PATIENTS GIVEN RECOMBINANT GP160 VACCINE PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Kundu, S. K., KATZENSTEIN, D., Moses, L. E., Merigan, T. C. 1992; 89 (23): 11204-11208

    Abstract

    Twenty-six human immunodeficiency virus (HIV)-infected asymptomatic patients with CD4+ lymphocytes > 400 per mm3 were randomly allocated to a range of doses of recombinant gp160 or a control (recombinant hepatitis B vaccine) on a double-blind basis. Each patient received an injection at 0, 4, 12, 24, 36, and 48 weeks. Treatment assignments were decoded when all patients reached 28 weeks of the study period. HIV-1-specific CD4+ and CD8+ cytotoxic T lymphocyte (CTL) activities were assessed in vitro before vaccination and 2 weeks after each injection. There were significant increases in major histocompatibility complex-restricted HIV-1 Env-specific CD4+ and CD8+ CTL activities in 18 of 21 gp160 vaccinees. No control-injected patients showed a significant change. Neither gp160 nor control recipients showed significant changes in HIV-1 Gag- and Pol-specific CTL activities. HIV-1 Env-specific CD4+ and CD8+ CTL precursor frequencies were also measured in three vaccinees before and at 24 weeks after vaccine was started. CTL precursor frequencies also increased in both CD4+ and CD8+ populations. This study shows that this gp160 vaccine is immunogenic in enhancing HIV-1 Env-specific cytotoxic T-cell-mediated immunity in HIV-seropositive individuals.

    View details for Web of Science ID A1992KA90300022

    View details for PubMedID 1360665

  • EQUIVALENT RECOGNITION OF HIV PROTEINS, ENV, GAG AND POL, BY CD4+ AND CD8+ CYTOTOXIC LYMPHOCYTES-T AIDS Kundu, S. K., Merigan, T. C. 1992; 6 (7): 643-649

    Abstract

    Cytotoxic T-lymphocytes (CTL) appear to be an important defense mechanism against HIV infection. This study proposes to examine the major histocompatibility complex (MHC)-restricted HIV-1 Env-, Gag- and Pol-specific CTL activities in HIV-infected asymptomatic patients.CD4+ and CD8+ CTL were examined to establish whether the same HIV-1 protein (Env, Gag or Pol) was recognized by both CD4+ and CD8+ CTL with MHC antigen restriction.Peripheral blood mononuclear cells, CD4+ and CD8+ T-cells from 17 HIV-infected asymptomatic patients and 10 HIV-seronegative individuals were examined for HIV-1 Env-, Gag- and Pol-specific MHC-restricted cytotoxicity using autologous and heterologous B-lymphoblastoid cell lines infected with vaccinia recombinant expressing HIV-1 Env, Gag and Pol proteins as targets.CD4+ and CD8+ CTL specific for the HIV-1 Env, Gag and Pol were demonstrated in the peripheral blood. DR4 and DQw2 were possible sites of MHC class II restriction of CD4+ CTL. Possible MHC class I restriction sites of CD8+ CTL included A2 and B8 for Env, A1 and A2 for Gag, and A2 and B8 for Pol antigen.These observations should help to define more precisely the nature and elements of protective immunity and to evaluate AIDS vaccine strategies.

    View details for Web of Science ID A1992JB68900005

    View details for PubMedID 1354446

  • Quantitative RNA and DNA gene amplification can rapidly monitor HIV infection and antiviral activity in cell cultures. PCR methods and applications Winters, M. A., Holodniy, M., Katzenstein, D. A., Merigan, T. C. 1992; 1 (4): 257-262

    Abstract

    We have developed a quantitative gene amplification procedure to assess the replication of human immunodeficiency virus (HIV) in cell cultures and evaluate the effect of drugs on viral replication. Increases in HIV gag RNA and DNA in phytohemagglutinin-stimulated normal peri-pheral blood mononuclear cells (PBMC) infected with HIV at very low multiplicity of infection paralleled the production of HIV p24 antigen in culture supernatants. Quantitative gene amplification was able to monitor the accumulation of viral nucleic acids in control cultures and demonstrate the effect of various concentrations of azidothymidine (AZT) on the replication of both AZT-sensitive and -resistant strains of HIV. The sensitivity of patient-derived virus strains to AZT could also be successfully measured by these procedures. The results of our studies suggest that quantitative measurement of HIV gag RNA and DNA can be used to monitor the kinetics of viral replication, antiviral activity, viral drug resistance, and mechanism of drug action.

    View details for PubMedID 1477661

  • A CONTROLLED TRIAL OF GANCICLOVIR TO PREVENT CYTOMEGALOVIRUS DISEASE AFTER HEART-TRANSPLANTATION NEW ENGLAND JOURNAL OF MEDICINE Merigan, T. C., Renlund, D. G., Keay, S., Bristow, M. R., Starnes, V., OCONNELL, J. B., Resta, S., Dunn, D., Gamberg, P., RATKOVEC, R. M., Richenbacher, W. E., Millar, R. C., Dumond, C., DEAMOND, B., Sullivan, V., CHENEY, T., Buhles, W., Stinson, E. B. 1992; 326 (18): 1182-1186

    Abstract

    Because of the immunosuppression required, heart-transplant recipients frequently have complications caused by cytomegalovirus (CMV), including pneumonia, esophagitis, gastritis, and a syndrome of fever, hepatitis, and leukopenia. We undertook a controlled trial to evaluate the prophylactic administration of ganciclovir to prevent CMV-induced disease after heart transplantation.This randomized, double-blind, placebo-controlled trial was conducted at four centers. Before randomization, the patients were stratified into two groups: those who were seropositive for CMV before transplantation and those who were seronegative but who received hearts from seropositive donors. Ganciclovir was given intravenously at a dose of 5 mg per kilogram of body weight every 12 hours from postoperative day 1 through day 14, then at a dose of 6 mg per kilogram each day for 5 days per week until day 28.Among the seropositive patients, CMV illness occurred during the first 120 days after heart transplantation in 26 of 56 patients given placebo (46 percent), as compared with 5 of 56 patients treated with ganciclovir (9 percent) (P less than 0.001). Among 37 seronegative patients, CMV illness was frequent in both groups (placebo, 29 percent; ganciclovir, 35 percent; P not significant). From day 15 through day 60, the patients who took ganciclovir had significantly fewer urine cultures positive for CMV, but by day 90 there was no difference. More of the ganciclovir-treated patients had serum creatinine concentrations greater than or equal to 221 mumol per liter (2.5 mg per deciliter) (18 percent vs. 4 percent in the placebo group), but those elevations were transient.The prophylactic administration of ganciclovir after heart transplantation is safe, and in CMV-seropositive patients it reduces the incidence of CMV-induced illness.

    View details for Web of Science ID A1992HR00800003

    View details for PubMedID 1313549

  • RESISTANCE TO INTERFERON-ALPHA IN A MOUSE B-CELL LYMPHOMA INVOLVES DNA METHYLATION JOURNAL OF INTERFERON RESEARCH Reid, T. R., Merigan, T. C., BASHAM, T. Y. 1992; 12 (2): 131-137

    Abstract

    Resistance to interferon-alpha (IFN-alpha) in the 38C13 B-lymphoma cell line results in the loss of antiviral, antiproliferative, and immune regulatory functions of IFN-alpha. Mutagenesis with ethylmethylsulfonic acid (EMS), which can induce point mutations in DNA, increases the frequency of resistance to IFN-alpha 20 to 40-fold. In contrast, treatment with 5-azacytidine, which causes hypomethylation of DNA, reduces the frequency of resistance to 5-10% of control. Furthermore, 5-azacytidine treatment reverts IFN-alpha-resistant cells to the IFN-alpha-sensitive state. Resistance to IFN-alpha occurs spontaneously at a rate of approximately 3 x 10(-6) variants/cell.generation, and is stable for more than 30 passages without selection in IFN-alpha. There is no evidence that gene amplification contributes to the high rate of resistance to IFN-alpha in these cells. These results indicate that DNA mutation and methylation are important in the development of IFN-alpha resistance in these cells.

    View details for Web of Science ID A1992HT11800009

    View details for PubMedID 1374455

  • CD8+CD11+ SUPPRESSOR CELLS IN HIV-INFECTED ASYMPTOMATIC PATIENTS - EFFECT ON HIV-SPECIFIC CYTOTOXICITY VIRAL IMMUNOLOGY Kundu, S. K., Merigan, T. C. 1992; 5 (1): 15-25

    Abstract

    CD3+CD8+CD11+ cells were present in the peripheral blood of patients infected with asymptomatic human immunodeficiency virus (HIV) in higher percentage (10-20%) than in normal individuals (3-5%) in this study. These cells, through the release of soluble factors, significantly suppressed the effector phase of anti-HIV cytotoxic activities, both human leukocyte antigen (HLA)-class I or class II restricted, and nonrestricted. The effectors were CD8+CD11-, CD4+ T cells, and CD16+ cells for HLA-class I, class II restricted, and nonrestricted cytotoxicities, respectively. The soluble factors also inhibited natural killer cell activity. Thus, this effect was neither HLA-restricted nor antigen-specific. These CD3+CD8+CD11+ cells may be an important immunopathogenic factor in HIV disease.

    View details for Web of Science ID A1992JE66900002

    View details for PubMedID 1351730

  • PLASMA VIREMIA IN HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION - RELATIONSHIP TO STAGE OF DISEASE AND ANTIVIRAL TREATMENT JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY Katzenstein, D. A., Holodniy, M., Israelski, D. M., Sengupta, S., Mole, L. A., BUBP, J. L., Merigan, T. C. 1992; 5 (2): 107-112

    Abstract

    Quantitative culture of human immunodeficiency virus (HIV) was performed on 121 plasma samples from 76 HIV-infected individuals to determine the sensitivity of the assay at different stages of disease and to measure the effect of antiviral therapy on plasma viremia. Plasma virus was detected in 49 of 76 (64%) of patients, primarily those with AIDS and AIDS-related complex (36 of 38) versus asymptomatic subjects (13 of 38) (p less than 0.001, chi 2). Similarly, plasma cultures were more often positive in patients with less than 250 CD4+ T cells per microliter (38 of 40) than in those with greater than 250 CD4+ T cells per microliter (11 of 36) (p less than 0.001, chi 2). Plasma virus cultures were also more likely to be positive in patients with detectable serum p24 antigen (24 of 26) than in those without detectable p24 antigen (25 of 50) (p = 0.0023, chi 2). An effect of zidovudine (ZDV) treatment on plasma viremia was seen in a comparison of treated and untreated patients with less than 250 CD4+ T cells per microliter. Geometric mean titers of plasma viremia from 16 patients treated with ZDV for more than 3 months were significantly lower than titers from 24 untreated patients (10(1.3) versus 10(2.1), p less than 0.05, Student's t test. A comparison of pre- and posttherapy titers in 33 patients receiving antiviral treatment showed that plasma virus was not detectable at either time in 17 patients; there was a fall in plasma virus titer in 12; and titers were unchanged or increased in 4. In patients with advanced disease, plasma viremia is a potential marker of antiviral drug activity.

    View details for Web of Science ID A1992GZ90200001

    View details for PubMedID 1732501

  • DECREASE IN HIV PROVIRUS IN PERIPHERAL-BLOOD MONONUCLEAR-CELLS DURING ZIDOVUDINE AND HUMAN RIL-2 ADMINISTRATION JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY Clark, A. G., Holodniy, M., Schwartz, D. H., Katzenstein, D. A., Merigan, T. C. 1992; 5 (1): 52-59

    Abstract

    Quantification of human immunodeficiency virus (HIV) proviral DNA in peripheral blood mononuclear cells (PBMC) was performed in 13 HIV-seropositive asymptomatic individuals during 10-24 months by polymerase chain reaction amplification of multiple half-log dilutions of cellular DNA. At enrollment, subjects had a geometric mean titer of 100 copies of HIV provirus per 10(6) PBMC (mean +/- SD, 2 +/- 0.9 log10). In four untreated individuals there was no significant change in provirus levels during a mean period of 13.3 months. In eight patients treated with zidovudine (ZDV) and human recombinant interleukin 2 (rIL-2), HIV provirus copies declined to 13 per 10(6) cells (1.1 +/- 0.8 log10) at the end of the first course of ZDV and rIL-2 at week 20 (p less than 0.01), and to 40 per 10(6) cells (1.6 +/- 0.9 log10) after 12 months of treatment (p less than 0.04). Subsequent courses, which included 12 weeks of ZDV alone or 4 weeks of IL-2 alone, did not significantly change the already depressed provirus copy numbers. Proviral copy number also remained depressed during drug-free "washout periods" between courses. Finally, we observed a return to a geometric mean of 400 copies per 10(6) cells (2.6 +/- 0.3 log10) a mean of 7.9 months after discontinuation of therapy. Measurement of changes in HIV provirus should provide a direct marker for defining antiviral activity of drugs, biologics, and combination therapy.

    View details for Web of Science ID A1992GW91300009

    View details for PubMedID 1738087

  • LIPOSOME-FORMULATED INTERLEUKIN-2 AS AN ADJUVANT OF RECOMBINANT HSV GLYCOPROTEIN GD FOR THE TREATMENT OF RECURRENT GENITAL HSV-2 IN GUINEA-PIGS VACCINE Ho, R. J., BURKE, R. L., Merigan, T. C. 1992; 10 (4): 209-213

    Abstract

    The use of interleukin-2 (IL-2) as an adjuvant to enhance an antigen-induced immunotherapeutic effect was investigated using guinea-pigs with established HSV-2 infection. Animals treated with four weekly doses of liposome-formulated IL-2 (2.7 x 10(5) U kg-1 dose) overlapping two biweekly doses of an HSV-recombinant glycoprotein D (rgD) treatment demonstrated approximately 70% reduction in HSV-2 recurrent disease compared with placebo (p less than 0.005). Combination therapy rgD plus liposome-formulated IL-2 exhibited approximately 30% greater therapeutic effect than either agent alone (p less than 0.05). Liposome formulation of IL-2 was essential to elicit the adjuvant effect. Identical biweekly dosing or more frequent daily dosing of soluble IL-2 did not produce additional therapeutic effects, suggesting the role of liposome targeting to lymph nodes. Although rgD plus liposome-formulated IL-2 induced a marginal early antibody response to rgD, there was no significant increase in overall antibody response. Combination therapy increased the frequency of minimally positive HSV lymphoproliferative response.

    View details for Web of Science ID A1992HF62500003

    View details for PubMedID 1561827

  • DETECTION AND QUANTIFICATION OF GENE AMPLIFICATION PRODUCTS BY A NONISOTOPIC AUTOMATED-SYSTEM BIOTECHNIQUES Holodniy, M., Winters, M. A., Merigan, T. C. 1992; 12 (1): 36-?

    Abstract

    We describe in this report the ability to determine human immunodeficiency virus proviral copy number by an automated nonisotopic method. Our system utilizes a FACStarPLUS cell sorter, the GeneAmp PCR System 9600 and a Biomek 1000 robotic workstation. Linking these three machines allows cell populations to be sorted and the DNA amplified and quantitated with minimal technical effort. We have developed this system to quantitate proviral DNA copy number in sorted subpopulations of peripheral blood cells in one day.

    View details for Web of Science ID A1992GZ18400006

    View details for PubMedID 1531177

  • INVERSE RELATIONSHIP OF CD8+CD11+ SUPPRESSOR T-CELLS WITH HUMAN-IMMUNODEFICIENCY-VIRUS (HIV)-SPECIFIC CELLULAR CYTOTOXICITY AND NATURAL-KILLER-CELL ACTIVITY IN HIV-INFECTION IMMUNOLOGY Kundu, S. K., Merigan, T. C. 1991; 74 (4): 567-571

    Abstract

    Profiles of CD8+CD11+ T suppressor cells, human immunodeficiency virus (HIV)-env-specific cytotoxic T-lymphocyte (CTL) activities, and natural killer (NK) cell activity were studied in 12 asymptomatic untreated HIV-infected patients. These patients were followed for 4-7 months. NK activity, HIV-env-specific CTL activities mediated by CD4+, CD8+ T cells and CD8+CD11+ T-suppressor cell number remained stable in seven patients during the study period. Alternatively, NK and HIV-specific CTL activities decreased and CD8+CD11+ cell number increased in five patients whose CD4+ T-cell number fell, and in four of these five patients serum p24 antigen level increased, and they developed minor clinical signs of disease progression during the study period. CD8+CD11+ cells are present in higher percentage (10-45% of peripheral blood mononuclear cells) in these HIV-infected patients as compared to those in normal individuals (3-5%). Our results suggest that CD8+CD11+ cells, NK, and HIV-specific cytotoxic activities may be helpful in monitoring prognosis of HIV infection. These observations also suggest that CD8+CD11+ cells may play an important role in the failure of host immune defences against HIV.

    View details for Web of Science ID A1991GV39300001

    View details for PubMedID 1686022

  • REDUCTION IN PLASMA HUMAN-IMMUNODEFICIENCY-VIRUS RIBONUCLEIC-ACID AFTER DIDEOXYNUCLEOSIDE THERAPY AS DETERMINED BY THE POLYMERASE CHAIN-REACTION JOURNAL OF CLINICAL INVESTIGATION Holodniy, M., Katzenstein, D. A., Israelski, D. M., Merigan, T. C. 1991; 88 (5): 1755-1759

    Abstract

    Cell-free HIV RNA in plasma was detected and quantitated after antiviral therapy by the polymerase chain reaction. RNA was extracted from plasma, reverse transcribed to cDNA, amplified by polymerase chain reaction, and quantitated by absorbance based on an enzyme-linked affinity assay. 72 HIV antibody-positive subjects had one plasma sample taken. 39 who were not receiving antiretroviral therapy at the time had a mean plasma HIV RNA copy number of 690 +/- 360 (mean +/- SEM) per 200 microliters of plasma, while 33 subjects who had been receiving zidovudine therapy for a minimum of 3 mo had a mean copy number of 134 +/- 219 (P less than 0.05). 27 additional HIV antibody-positive patients had two plasma samples taken before and 1 mo after initiating dideoxynucleoside therapy. Plasma HIV RNA copy number fell from 540 +/- 175 to 77 +/- 35 (P less than 0.05). Finally, nine of these subjects had two baseline samples obtained before initiating therapy and two posttreatment samples 1 and 2 mo after therapy was begun. Mean plasma RNA copy number declined from 794 +/- 274 to less than 40 (below the lower limit of sensitivity) after 1 mo of therapy, with suppression maintained after 2 mo of therapy. These results suggest that gene amplification can be used to detect and quantitate changes in plasma HIV RNA after dideoxynucleoside therapy. Plasma HIV polymerase chain reaction may be a more sensitive marker to monitor antiviral therapy, particularly in asymptomatic patients where measurement of p24 antigen or quantitative plasma cultures are negative.

    View details for Web of Science ID A1991GN72700044

    View details for PubMedID 1682345

  • ANTIBODY-RESPONSE TO HUMAN CYTOMEGALOVIRUS GLYCOPROTEIN-GB AND GLYCOPROTEIN-GH AFTER NATURAL INFECTION IN HUMANS JOURNAL OF INFECTIOUS DISEASES Rasmussen, L., Matkin, C., Spaete, R., PACHL, C., Merigan, T. C. 1991; 164 (5): 835-842

    Abstract

    Antibody to the recombinant gB (rgB) and recombinant gH (rgH) glycoproteins of human cytomegalovirus (CMV) was studied in immunocompetent and immunocompromised humans by immunoprecipitating [35S]methionine-labeled CHO cell lines stably expressing rgB and rgH. Antibody to the rgB precursor was present in greater than 60% of immunocompetent individuals. However rgH antibody was detected in less than 10% of these patients. Antibody to both the rgB and rgH was detected during convalescence in three immunocompetent individuals with symptomatic CMV mononucleosis but to a lesser extent in three others who seroconverted to CMV without symptoms. Antibody to rgB and rgH in heart and heart-and-lung transplant recipients was detected in both primary and recurrent CMV infections but not with the same intensity as in immunocompetent individuals. Selected lots of immune serum globulin, administered prophylactically to bone marrow transplant recipients, were frequently deficient in antibody to rgH but not to rgB.

    View details for Web of Science ID A1991GL29400001

    View details for PubMedID 1658156

  • DETECTION OF HUMAN-IMMUNODEFICIENCY-VIRUS DNA AND RNA IN SEMEN BY THE POLYMERASE CHAIN-REACTION JOURNAL OF INFECTIOUS DISEASES Mermin, J. H., Holodniy, M., Katzenstein, D. A., Merigan, T. C. 1991; 164 (4): 769-772

    Abstract

    Peripheral blood mononuclear cells (PBMC) and semen of 23 men infected with human immunodeficiency virus (HIV) were examined for the presence of HIV DNA and RNA using the polymerase chain reaction (PCR) and a nonisotopic detection assay. None of the men was receiving antiretroviral therapy at the time of collection. Semen samples were separated into cell-free seminal fluid, nonspermatozoal mononuclear cells (NSMC), and spermatozoa. All of the PBMC samples, 17 (74%) of 23 NSMC samples, and none of the spermatozoal samples were positive for HIV gag gene DNA. Of 23 cell-free seminal fluid samples, 15 (65%) were positive for HIV gag gene RNA by PCR. Cell-free HIV RNA was more likely to be present in the semen of men with less than 400 than in those with greater than or equal to 400 cells/mm3 (P less than .04) and was present in all patient with p24 antigen in serum. The presence of HIV DNA in NSMC samples was not related to CD4 cell count, disease status, or the presence of p24 antigen in the serum. This study shows that HIV nucleic acid can be detected by PCR in either the cell-free seminal fluid or NSMC of 87% of semen samples but not in the DNA of spermatozoa from HIV-infected men.

    View details for Web of Science ID A1991GF80500022

    View details for PubMedID 1680138

  • PLACEBO-CONTROLLED TRIAL TO EVALUATE ZIDOVUDINE IN TREATMENT OF HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION IN ASYMPTOMATIC PATIENTS WITH HEMOPHILIA BLOOD Merigan, T. C., Amato, D. A., Balsley, J., Power, M., Price, W. A., Benoit, S., PEREZMICHAEL, A., Brownstein, A., KRAMER, A. S., Brettler, D., Aledort, L., Ragni, M. V., Andes, W. A., Gill, J. C., Goldsmith, J., Stabler, S., Sanders, N., GJERSET, G., Lusher, J. 1991; 78 (4): 900-906

    Abstract

    One hundred ninety-three asymptomatic patients with hereditary coagulation disorders and human immunodeficiency virus (HIV) infection were studied in a controlled trial of zidovudine (ZDV) versus a placebo (with an average of 9.7 months on study). Pretreatment characteristics were well balanced between the placebo and drug-treated groups, including CD4 distributions, types of clotting disorders, transaminase abnormalities, and use of various hemostatic agents. At the time of analysis, 161 patients either were still receiving treatment or had previously reached an endpoint of disease progression while receiving treatment. Twenty-five patients withdrew voluntarily. The toxic effects noted included granulocytopenia and anemia, especially in older patients, and subjective symptoms of asthenia, malaise, and nausea, consistent with the known consequences of treatment with 300 mg ZDV five times daily. There was a trend toward more diagnoses of acquired immunodeficiency syndrome (AIDS), advanced or early AIDS-related complex (ARC), single ARC symptoms, or death in placebo recipients as compared with those receiving ZDV (22 v 13). Because older patients with hemophilia have more rapid disease progression, the same efficacy analysis was performed in the 89 patients aged more than 30 years who were receiving treatment. In this subgroup, there was a similar trend (11 v 6). With regard to the most advanced problems of the infection among the older patients, there were five patients who were newly diagnosed with AIDS or died in the placebo group versus none in the ZDV group (P = .02) among the older patients. The pretreatment distribution of CD4 counts for the placebo and ZDV groups were similar, but patients aged more than 30 years had significantly (P less than .049) fewer CD4 cells than patients aged less than 30 years. A beneficial ZDV effect is also supported by a trend toward higher CD4 counts (a 48-cell increase in the ZDV group at 24 weeks as compared with a four-cell increase in the placebo group) and a significant (P = .03) difference in weight gain in the ZDV patients aged more than 30 years (8 pounds) as compared with the older placebo patients (aged more than 30 years) (2 pounds) at week 24. The findings in the asymptomatic hemophilic patients aged more than 30 years support a useful effect of ZDV, which is similar to observations in the larger study of its use in asymptomatic, nonhemophilic patients.

    View details for Web of Science ID A1991GB20800005

    View details for PubMedID 1831059

  • CYTOMEGALOVIRUS-SPECIFIC CELL-MEDIATED IMMUNE-RESPONSES IN HEART AND HEART LUNG-TRANSPLANT RECIPIENTS ARE NOT PREDICTIVE FOR THE OCCURRENCE OF SYMPTOMATIC CMV DISEASE OR TISSUE REJECTION JOURNAL OF INTERFERON RESEARCH VANTIEL, F. H., Rasmussen, L., Merigan, T. C. 1991; 11 (4): 221-229

    Abstract

    To study the predictive value of interferon-gamma (IFN-gamma) production in vitro for the occurrence of symptomatic CMV disease, 17 healthy adult volunteers were tested and 37 heart or heart-lung transplant recipients (CTRs) were studied at various time intervals after transplantation (Tx) for cell-mediated immune (CMI) responses to cytomegalovirus (CMV). At all intervals post Tx, in vitro IFN-gamma production in CTRs was significantly lower than in control subjects. The occurrence of CMV infection was associated with a trend toward inhibited CMI responses prior to the diagnosis, in comparison with CMI responses measured more than 4 weeks prior to or after the diagnosis of CMV infection. The occurrence of acute tissue rejection was associated with a trend toward enhanced CMV responses prior to the diagnosis, on the other hand. In the early post Tx period, the administration of antithymocyte globulin (ATG) or OKT3 monoclonal antibody and peak dosages of azathioprine were associated with significantly inhibited in vitro IFN-gamma production. Despite the demonstrated trends in vitro, IFN-gamma production does not appear to be uniformly predictive for the occurrence of symptomatic CMV disease or of acute tissue rejection in CTRs.

    View details for Web of Science ID A1991GA41500004

    View details for PubMedID 1655916

  • ANTIVIRAL ACTIVITY AND DOSE OPTIMUM OF RECOMBINANT MACROPHAGE COLONY-STIMULATING FACTOR ON HERPES-SIMPLEX GENITALIS IN GUINEA-PIGS JOURNAL OF IMMUNOLOGY Ho, R. J., Chong, K. T., Merigan, T. C. 1991; 146 (10): 3578-3582

    Abstract

    The antiviral activity of recombinant human macrophage CSF (M-CSF) against genital herpes simplex virus type-2 (HSV-2) infection in guinea pigs was investigated. M-CSF stimulates proliferation of human and guinea pig peripheral blood monocytes, specifically the plastic adherent esterase-positive mononuclear cells. When anti-HSV-2 activity of M-CSF was evaluated in guinea pigs by 6 daily injection (s.c.) of M-CSF at various doses (5 x 10(5) to 7 x 10(7) U/kg), we found 2 x 10(6) U/kg to be the optimum dose for protective efficacy against primary HSV-2 infection. Either at a lethal, 5 x 10(5) pfu, or sublethal 5 x 10(4) pfu of virus challenge, animals treated with the optimum regimen of M-CSF exhibited lower herpetic lesion scores (p less than 0.005), and lower mortality (p less than 0.025) than animals in placebo group. M-CSF treatment increased the HSV-infected cell killing activities of plastic-adherent mononuclear cells, indicating that in vivo administration of M-CSF may activate the antiviral effects of guinea pig macrophages that may play a role in protection against severity and mortality of herpetic disease.

    View details for Web of Science ID A1991FL83600044

    View details for PubMedID 1851195

  • Treatment of AIDS with combinations of antiretroviral agents. American journal of medicine Merigan, T. C. 1991; 90 (4A): 8S-17S

    Abstract

    Although 3'-azido-3'-deoxythymidine (zidovudine, AZT) has demonstrated efficacy in the treatment of human immunodeficiency virus (HIV) infection, there are limitations associated with its use. Consequently, other agents, such as 2',3'-dideoxycytidine (ddC) and 2',3'-dideoxyinosine (ddI), are being assessed for the treatment of patients with HIV infection. However, the most effective therapy for HIV infection may be combination therapy with zidovudine and any of a number of other therapies. To obtain maximum efficacy, combination regimens should include agents that do not share cross-resistance, have different mechanisms of action, and have different dose-limiting toxicities; the relative merits of a concurrent dosage schedule (limits drug failure) and a consecutive dosage schedule (limits toxicity) must also be considered. In addition, the shift between administering a starting regimen and a rescue regimen should be based on time on therapy, disease breakthrough, or drug complication. Eventually, the shift may be precipitated by the in vitro resistance patterns of individual viruses, as is now the case with antibiotics for infection. Several trials are currently in progress to assess combination therapy with zidovudine and ddC; initial results indicate that the combination may allow for improved efficacy and decreased side effects, compared with treatment with either drug alone. Trials of combination therapy with ddI, interferon alfa, and acyclovir are also in progress. It is hoped that these initial studies will pave the way for rational drug sequencing in the treatment of patients with acquired immunodeficiency syndrome.

    View details for PubMedID 1850192

  • ABSENT OR RARE HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION OF BONE-MARROW STEM PROGENITOR CELLS INVIVO JOURNAL OF VIROLOGY Davis, B. R., Schwartz, D. H., Marx, J. C., Johnson, C. E., Berry, J. M., Lyding, J., Merigan, T. C., Zander, A. 1991; 65 (4): 1985-1990

    Abstract

    An important question in human immunodeficiency virus (HIV) pathogenesis is whether HIV-infected bone marrow CD34+ stem/progenitor cells serve as a significant reservoir of virus in HIV-infected individuals. Our data indicate that infection of bone marrow stem/progenitor cells with HIV occurs rarely, if ever, in vivo. In the present study, CD34+ cells were immunomagnetically purified from the bone marrow of HIV-seropositive individuals, and purified cells or colony-forming cells of the granulocyte/macrophage lineage were analyzed for HIV proviral DNA by the polymerase chain reaction. No HIV DNA was detected in colony-forming cells of the granulocyte/macrophage lineage from HIV-positive patients. Furthermore, no virus was found in CD34(+)-enriched cells from six of seven samples from asymptomatic HIV-infected individuals and four of four samples from patients with AIDS-related complex or AIDS. Thus, infected stem cells are not a major source of persistent HIV and do not account for hematopoietic suppression. These findings have positive implications for the concept of marrow reconstitution with autologous stem cells, genetically engineered for HIV resistance, following marrow-ablative antiviral therapy.

    View details for Web of Science ID A1991FC03100041

    View details for PubMedID 2002553

  • INTERMITTENT, ALTERNATING, AND CONCURRENT REGIMENS OF ZIDOVUDINE AND 2'-3'DIDEOXYCYTIDINE IN THE LP-BM5 MURINE INDUCED IMMUNODEFICIENCY MODEL JOURNAL OF INFECTIOUS DISEASES BASHAM, T., HOLDENER, T., Merigan, T. 1991; 163 (4): 869-872

    Abstract

    The murine retrovirus-induced immunodeficiency model, LP-BM5, was used to evaluate the efficacy of intermittent and alternating regimens of zidovudine (azido-2'-3'dideoxythymidine; AZT) and 2'-3' dideoxycytidine (ddC) compared with continuous and concurrent therapy. Intermittent oral AZT therapy was less effective in protecting mice inoculated with LP-BM5 virus than was continuous oral AZT therapy. Continuous oral ddC therapy (80 mg/kg/day) increased survival time an average of 3.5 weeks (P less than .001) compared with that in untreated LP-BM5-infected mice. Alternating weekly AZT and ddC therapy, which increased survival time 3.5 weeks (P less than .001), was more effective than either therapy administered intermittently, although not additive or synergistic. Concurrent AZT and ddC therapy was no more effective than continuous AZT therapy alone in this model, with a 4.4-week increase in survival time (P less than .001).

    View details for Web of Science ID A1991FD93900033

    View details for PubMedID 1849164

  • DETECTION AND QUANTIFICATION OF HUMAN-IMMUNODEFICIENCY-VIRUS RNA IN PATIENT SERUM BY USE OF THE POLYMERASE CHAIN-REACTION JOURNAL OF INFECTIOUS DISEASES Holodniy, M., Katzenstein, D. A., Sengupta, S., Wang, A. M., CASIPIT, C., Schwartz, D. H., Konrad, M., Groves, E., Merigan, T. C. 1991; 163 (4): 862-866

    Abstract

    Human immunodeficiency virus (HIV) RNA was detected and quantified in the serum of HIV-seropositive individuals using the polymerase chain reaction (PCR) and a nonisotopic enzyme-linked affinity assay. Of 55 HIV-infected patients who were not receiving therapy, serum HIV RNA was detected in 9 of 19 who were asymptomatic, 11 of 16 with AIDS-related complex (ARC), and 18 of 20 with AIDS, with copy numbers ranging from 10(2) to greater than or equal to 5 x 10(4) 200 microliters of serum based on a relationship between absorbance and known copy number of gag gene RNA. Linear regression analysis demonstrated a correlation between infectious titer in 42 patient sera cocultured with donor peripheral blood mononuclear cells (PBMC) and PCR product absorbance (r = .70, P less than .01). Serum HIV RNA detected by PCR also correlated with serum p24 antigen positivity, CD4 counts less than 400/mm3, and the presence of HIV-related symptoms or disease. Quantification of infectious HIV RNA in cell-free serum by PCR may be useful as a marker for for disease progression or in monitoring antiviral therapy.

    View details for Web of Science ID A1991FD93900031

    View details for PubMedID 2010639

  • INHIBITION OF HUMAN-IMMUNODEFICIENCY-VIRUS GENE AMPLIFICATION BY HEPARIN JOURNAL OF CLINICAL MICROBIOLOGY Holodniy, M., Kim, S., KATZENSTEIN, D., Konrad, M., Groves, E., Merigan, T. C. 1991; 29 (4): 676-679

    Abstract

    Gene amplification of virus-specific sequences is widely used as a method to detect or confirm human immunodeficiency virus (HIV) infection. In this study we used an enzyme-linked affinity assay to quantify polymerase chain reaction products from whole blood, plasma, and separated mononuclear cells collected in the presence of four common anticoagulants: acid citrate dextrose, sodium EDTA, potassium oxalate, and sodium heparin. Attenuation of the product signal was observed after amplification of nucleic acid extraction from whole blood, washed mononuclear cells, and plasma from specimens collected in sodium heparin. These inhibitory effects on gene amplification could be reversed with heparinase. The addition of as little as 0.05 U of heparin completely inhibited amplification of an HLA-DQa sequence from placental DNA. We conclude that heparin can cause attenuation or inhibition of gene amplification. Acid citrate dextrose and EDTA, which lack inhibitory activity, are the most appropriate anticoagulants for clinical blood samples when polymerase chain reaction amplification is anticipated.

    View details for Web of Science ID A1991FC91900003

    View details for PubMedID 1909709

  • RELATION OF THE PATHOGENESIS OF HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION TO VARIOUS STRATEGIES FOR ITS CONTROL REVIEWS OF INFECTIOUS DISEASES Merigan, T. C., Katzenstein, D. A. 1991; 13 (2): 292-302

    Abstract

    This paper reviews functionally important insights into the pathogenesis of human immunodeficiency virus (HIV) infection. The major sequela of this infection is early and progressive involvement of the immune system, with widespread immune dysfunction. This pathogenetic feature has a major impact on strategies for control of the infection. The immunosuppression caused by the virus leads to higher levels of viral replication and enhanced potential for development or selection of variant viruses, including forms that are more virulent or even drug resistant. Therefore, control of HIV infection and disease may require antiviral agents and CD4 receptor competitors as well as recombinant DNA-derived lymphokines and subunit vaccine immunotherapies. To be successful, such therapies must work to counter infection in monocytes and nonlymphoid cells as well as in T4 lymphocytes. Because many limbs of the immune system are affected by HIV infection, the complexities of this pathogen can be unraveled only by the careful study of immune functions during the disease and of effective interventions to control infection and disease and to restore immune functions.

    View details for Web of Science ID A1991FD04700018

    View details for PubMedID 2041962

  • SAFETY AND EFFECTS OF INTERLEUKIN-2 PLUS ZIDOVUDINE IN ASYMPTOMATIC INDIVIDUALS INFECTED WITH HUMAN-IMMUNODEFICIENCY-VIRUS JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY Schwartz, D. H., Skowron, G., Merigan, T. C. 1991; 4 (1): 11-23

    Abstract

    The safety of continuous i.v. interleukin-2 (IL-2) in conjunction with zidovudine (ZDV) was assessed in asymptomatic patients infected with human immunodeficiency virus. Clinical, immunologic, and viral parameters were monitored in a phase I/II trial with dose escalation and crossover arms. Daily doses of IL-2 from 1.5 to 12 x 10(6) IU/m2 were well tolerated and, in the presence of ZDV, did not induce increases in p24 antigenemia. Significant (p less than 0.05) but transient increases in CD4 cells were observed midway through infusion of IL-2 at all doses, and increases in natural and lymphokine-activated killer activity were seen at higher doses. Circulating hypodense eosinophils and soluble IL-2 receptors increased more than 10-fold. Of nine patients available for long-term follow up 13-25 months from baseline and 4-21 months after stopping IL-2, six still had improved CD4 counts (versus baseline), and the mean increase (135/mm3) for all nine patients was significant (p less than 0.05). Eight of these nine patients were negative for serum p24 at the start of therapy, and none had become p24 antigenemic at long-term follow-up.

    View details for Web of Science ID A1991EP17600002

    View details for PubMedID 1670586

  • YOU CAN TEACH AN OLD DOG NEW TRICKS - HOW AIDS TRIALS ARE PIONEERING NEW STRATEGIES NEW ENGLAND JOURNAL OF MEDICINE Merigan, T. C. 1990; 323 (19): 1341-1343

    View details for Web of Science ID A1990EG58800011

    View details for PubMedID 1977082

  • ACUTE DELTA HEPATITIS DURING TREATMENT WITH ADENOSINE ARABINOSIDE MONOPHOSPHATE WITH RESOLUTION OF THE HBSAG CARRIER STATE WESTERN JOURNAL OF MEDICINE Garcia, G., Smedile, A., BERGMANN, K. F., Gerin, J. L., Gregory, P. B., Merigan, T. C., Robinson, W. S. 1990; 153 (1): 80-82

    View details for Web of Science ID A1990DQ62200023

    View details for PubMedID 1697132

  • Alternating and intermittent regimens of zidovudine (3'-azido-3'-deoxythymidine) and dideoxycytidine (2',3'-dideoxycytidine) in the treatment of patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. American journal of medicine Skowron, G., Merigan, T. C. 1990; 88 (5B): 20S-23S

    Abstract

    The deoxynucleoside analogues 2',3'-dideoxy-cytidine (ddC) and 3'-azido-3'-deoxythymidine (zidovudine, AZT) are active as single agents in conferring immunologic and virologic benefits in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex. Both drugs, however, produce dose-limiting toxicities. AZT is associated with unacceptable levels of bone marrow suppression, and ddC can cause painful peripheral neuropathy. The different toxicity profiles of these two drugs provide the rationale for testing them in alternating dosing combinations in an attempt to retain the antiretroviral activity of each against human immunodeficiency virus, while reducing the toxicities of both. A preliminary trial showed that 200 mg AZT given orally every four hours for seven-day periods, alternating with ddC at 0.03 mg/kg body weight orally every four hours for seven-day periods is a promising treatment regimen. An expanded multicenter study is evaluating ddC at 0.01 mg/kg and 0.03 mg/kg alternating with AZT at 200 mg in weekly or monthly periods. Weekly intermittent doses of AZT at 200 mg and ddC at 0.03 mg/kg are also being tested. The rationale and methods of the trial are discussed.

    View details for PubMedID 2159705

  • Safety and tolerance of dideoxycytidine as a single agent. Results of early-phase studies in patients with acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex. Study Group of the AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases. American journal of medicine Merigan, T. C., Skowron, G. 1990; 88 (5B): 11S-15S

    Abstract

    Phase I and II clinical studies have been conducted to test the safety and potential activity of the reverse transcriptase inhibitor, dideoxycytidine (ddC), in treating human immunodeficiency virus-1-infected patients. Although ddC appears to be active in combating viral infection, as judged by its ability to decrease human immunodeficiency virus-1 p24 antigen titers and increase the number of CD4+ lymphocytes, it is also capable of causing severe peripheral neuropathy in a dose-dependent manner. The studies discussed here indicate that low-dose ddC treatment regimens substantially reduce the toxic side effects of this drug, and yet retain the ability to affect p24 antigen and CD4+ lymphocyte levels. These studies also define the window of therapeutic usefulness for ddC, and suggest that both safety and activity can be maintained during long-term, low-dose use of ddC.

    View details for PubMedID 2159703

  • ZIDOVUDINE (AZT) REDUCES VIRUS TITER, RETARDS IMMUNE DYSFUNCTION, AND PROLONGS SURVIVAL IN THE LP-BM5 MURINE INDUCED IMMUNODEFICIENCY MODEL JOURNAL OF INFECTIOUS DISEASES BASHAM, T., Rios, C. D., HOLDENER, T., Merigan, T. C. 1990; 161 (5): 1006-1009

    Abstract

    Using the murine LP-BM5 retrovirus-induced immunodeficiency model, the therapeutic value of zidovudine (AZT) was analyzed. Continuous low dose (60 mg/kg per day) oral AZT administration for 6 weeks increased survival time by 5-6 weeks. Decreasing the duration of therapy to 3 weeks decreased the mean survival time. Extending the therapy from 6 to 14 weeks increased the median survival time (8 weeks). This dose was nontoxic and reduced virus titers, splenomegaly, and lymphadenopathy. AZT also retarded the immune dysfunction syndrome characteristic of this model. Hypergammaglobulinemia was reduced by AZT and was also a marker for disease progression. AZT reduced hyperproliferation of large blast cells and delayed the loss of splenic B cells.

    View details for Web of Science ID A1990DB18400031

    View details for PubMedID 2157768

  • PHYSICAL AND BIOLOGICAL CHARACTERIZATION OF ANTIGEN PRESENTING LIPOSOME FORMULATIONS - RELATIVE EFFICACY FOR THE TREATMENT OF RECURRENT GENITAL HSV-2 IN GUINEA-PIGS ANTIVIRAL RESEARCH Ho, R. J., BURKE, R. L., Merigan, T. C. 1990; 13 (4): 187-200

    Abstract

    Antigen presenting liposomes (APLs) containing both liposome encapsulated (44%) and free (56%) recombinant glycoprotein D of herpes simplex virus type-2 (rgD-2) were characterized with respect to the interaction of the antigen with the lipid bilayer and the biological activities provided by each form of rgD-2. We found that free rgD-2 added externally to empty liposomes exhibited some biological activities both in vitro and in vivo, although we could not detect any significant adsorption and/or insertion of this form of rgD-2 into the lipid bilayer. Compared to APLs containing both forms of rgD-2, purified liposomes containing only encapsulated rgD-2 gave only 50% of the relative activity in vitro as measured by their ability to stimulate rgD-2 specific lymphocyte proliferation, and 67% of the relative activity in vivo as measured by their immunotherapeutic effect on recurrent genital HSV-2 disease in guinea pigs (P less than 0.05). These data indicate that while liposome encapsulated rgD-2 is essential for the elicitation of immunogenic responses, the free soluble rgD-2 in the APL formulation also acts in concert to generate an optimum immunotherapeutic efficacy.

    View details for Web of Science ID A1990DF06900004

    View details for PubMedID 2383000

  • ZIDOVUDINE (AZIDO DIDEOXYTHYMIDINE) INHIBITS CHARACTERISTIC EARLY ALTERATIONS OF LYMPHOID-CELL POPULATIONS IN RETROVIRUS-INDUCED MURINE AIDS JOURNAL OF IMMUNOLOGY Portnoi, D., STALL, A. M., Schwartz, D., Merigan, T. C., Herzenberg, L. A., BASHAM, T. 1990; 144 (5): 1705-1710

    Abstract

    Using flow cytometry technology and multiparameter analyses, we report early and characteristic alterations in lymphoid cell profile in spleen and lymph nodes due to LP-BM5 retrovirus disease (murine AIDS (MAIDS)) and the effect of azido dideoxythymidine, a nucleoside inhibitor, on these changes. MAIDS has been characterized by rapid and profound lymphoproliferation accompanied by hypergammaglobulinemia and immunosuppression. As early as 2 wk postinfection, there is a selective depletion of CD8+ cells whereas the total number of CD4+ cells increases throughout the first 8 wk of infection although the frequency is relatively stable. These population changes were partially delayed by oral AZT therapy for 6 wk postinfection. Ly-6C (AL-21) is expressed on roughly 50% of CD4+ and CD8+ cells in C57BL/6 mice. In MAIDS, the residual population of CD8+ cells is primarily Ly-6C+. The CD4+ cells have a transient increase in ratio of Ly-6C+/Ly-6C- cells at 2 wk postinfection but by 6 wk are primarily Ly-6C-. There was an increase in both the total number and percentage of Mac 1+ cells and a selective depletion of certain splenic B cell subpopulations. Azido dideoxythymidine delays these early population changes.

    View details for Web of Science ID A1990CR42900022

    View details for PubMedID 1968486

  • Recombinant soluble CD4 therapy in patients with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. A phase I-II escalating dosage trial. Annals of internal medicine Schooley, R. T., Merigan, T. C., Gaut, P., Hirsch, M. S., Holodniy, M., Flynn, T., Liu, S., BYINGTON, R. E., Henochowicz, S., Gubish, E. 1990; 112 (4): 247-253

    Abstract

    To study the safety and pharmacokinetics and to derive preliminary evidence on surrogate indicators of efficacy of recombinant soluble CD4 (rsCD4) in patients with the acquired immunodeficiency syndrome (AIDS) and advanced AIDS-related complex.Open label, escalating dosage, phase I-II tolerance trial.Massachusetts General Hospital, Cedars-Sinai Medical Center, and Stanford University Medical School, three tertiary care institutions and members of the National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group. INSTRUCTIONS: Cohorts of 3 to 11 patients received rsCD4 by intravenous infusion or intramuscular injection in dosages of up to 30 mg per day for 28 days. MEASUREMENTS andRecombinant soluble CD4 was tolerated by these patients with no significant clinical or immunologic toxicities. Serum levels of rsCD4 in patients receiving doses of 9 or 30 mg per day administered intramuscularly were in the range of rsCD4 concentrations required to inhibit replication of human immunodeficiency virus 1 (HIV-1) in vitro. A decline in serum HIV-1 p24 antigen was seen in patients receiving 30 mg of rsCD4 daily, but no such changes were noted at lower dosages.Recombinant soluble CD4 is well tolerated by patients with AIDS or advanced AIDS-related complex. Our study has also provided preliminary evidence of antiviral activity of rsCD4 in vivo. Our data suggest that further trials of receptor-based therapies against HIV-1 are warranted.

    View details for PubMedID 2297203

  • CLINICAL-TRIALS OF COMBINATION THERAPIES FOR HIV-INFECTION - DISCUSSION JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY McGowan, J., Merigan, T., Sherwin, S. 1990; 3: S108-S110

    View details for Web of Science ID A1990EL48100025

    View details for PubMedID 2172505

  • Interleukin-2 in the treatment of HIV disease. Biotherapy Schwartz, D. H., Merigan, T. C. 1990; 2 (2): 119-136

    View details for PubMedID 2205261

  • IDENTIFICATION OF CELL-SURFACE RECEPTORS FOR THE 86-KILODALTON GLYCOPROTEIN OF HUMAN CYTOMEGALO-VIRUS PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Keay, S., Merigan, T. C., Rasmussen, L. 1989; 86 (24): 10100-10103

    Abstract

    Cell surface receptors for the 86-kDa glycoprotein (gp86) of human cytomegalovirus (HCMV) were identified by using two monoclonal anti-idiotype antibodies that bear the internal image of gp86. These antibodies bound to cells permissive for HCMV infection by both ELISA and immunofluorescence assay and inhibited HCMV plaque formation in human embryonic lung (HEL) cells. Immunoblot analysis showed specific binding of both internal image anti-idiotype antibodies as well as gp86 to an HEL cell membrane protein with an approximate molecular mass of 92.5 kDa. In addition, immunoprecipitation of radiolabeled membrane and cell surface proteins from human foreskin tissue, human foreskin fibroblasts, or HEL cells showed specific binding of anti-idiotype antibody predominantly to the 92.5-kDa protein.

    View details for Web of Science ID A1989CE97600097

    View details for PubMedID 2557618

  • PHARMACOKINETICS OF RIFABUTIN ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Skinner, M. H., Hsieh, M., TORSETH, J., PAULOIN, D., Bhatia, G., Harkonen, S., Merigan, T. C., Blaschke, T. F. 1989; 33 (8): 1237-1241

    Abstract

    We investigated the pharmacokinetics of rifabutin in 15 male patients as part of a phase I trial of the treatment of early symptomatic human immunodeficiency virus infection. Six or more patients were studied at each of four different oral dosage levels: 300, 600, 900, and 1,200 mg/day. Twelve studies were also conducted with tracer doses of intravenous radiolabeled [14C]rifabutin. Blood and urine samples were collected for at least 72 h after the first (day 1) and last (day 28) doses of rifabutin and analyzed by high-pressure liquid chromatography. The plasma concentration data were best described by a two-compartment open model with a terminal half-life of 36 h. Rifabutin was rapidly absorbed, reaching a peak concentration about 2 to 3 h after an oral dose. Peak and trough concentrations for the 1,200-mg dose were 907 and 194 ng/ml, respectively. Total body clearance was 10 to 18 liters/h. Oral bioavailability was 12 to 20%. The drug was moderately bound to plasma proteins with a free fraction of 29 +/- 2% (mean +/- standard deviation). About 10% of an administered intravenous dose of rifabutin is excreted into the urine unchanged. Renal clearance was 1.5 +/- 0.2 liters/h. The volume of distribution was large (8 to 9 liters/kg), suggesting extensive distribution into the tissues. The area under the curve for the last dose was smaller than that of the first dose, suggesting possible induction of drug-metabolizing enzymes.

    View details for Web of Science ID A1989AJ32000020

    View details for PubMedID 2552902

  • ENHANCED INVIVO THERAPEUTIC RESPONSE TO INTERFERON IN MICE WITH AN INVITRO INTERFERON-RESISTANT B-CELL LYMPHOMA CANCER RESEARCH Reid, T. R., RACE, E. R., WOLFF, B. H., Friedman, R. M., Merigan, T. C., BASHAM, T. Y. 1989; 49 (15): 4163-4169

    Abstract

    A stable subline of 38C13 B-cell lymphoma (SIR-1) resistant to the antiproliferative effects of alpha-interferon (IFN) was isolated. In addition to defects in antiproliferative effects of IFN, SIR-1 is defective in IFN-mediated antiviral activity against both encephalomyocarditis virus and vesicularstomatitis virus. It is also defective in the induction of 2'-5'-oligoadenylate synthetase mRNA and enzyme activity, enhancement of H-2 antigen expression, and transient induction and subsequent repression of c-myc by IFN. SIR-1, although completely resistant to IFN in vitro, is more sensitive to IFN than the parental cell line in vivo. IFN treatment at 10(4) units, three times weekly, resulted in a 28% increase in mean survival time and a 1.4% long term survival rate in the IFN-sensitive 38C13 cell line but resulted in a 275% increase in mean survival rate and a 27% long term survival rate in the interferon-resistant SIR-1 mutant. Statistical analysis of 38C13 and SIR-1 with and without IFN treatment demonstrate that: a) the SIR-1 mutant remains sensitive to the cytotoxic effects of IFN in vivo (P less than 0.0001); and b) the mean survival and long term survival of animals with the SIR-1 mutant is significantly greater than for animals with the IFN-sensitive 38C13 cell line (P less than 0.0001). Two additional independently isolated IFN-resistant cell lines (SIR-111 and SIR-E102) also demonstrate significantly enhanced in vivo response to IFN compared to the interferon-sensitive parental (38C13) cells. These results indicate that, for this cell line, the antitumor effects of IFN are mediated by activation of host defenses and that resistance to the in vitro cytotoxic effects of IFN results in a tumor phenotype that is more readily recognized by host defenses and eliminated.

    View details for Web of Science ID A1989AG30700018

    View details for PubMedID 2787203

  • ANTIGEN-PRESENTING LIPOSOMES ARE EFFECTIVE IN TREATMENT OF RECURRENT HERPES-SIMPLEX VIRUS GENITALIS IN GUINEA-PIGS JOURNAL OF VIROLOGY Ho, R. J., BURKE, R. L., Merigan, T. C. 1989; 63 (7): 2951-2958

    Abstract

    The therapeutic and immunologic effects of a liposome preparation containing both a macrophage activator, muramyl-tripeptide-phosphatidylethanolamine, and a recombinant antigen, glycoprotein D of herpes simplex virus type 1, have been investigated. This preparation was tested in vitro for the ability to stimulate peripheral blood lymphocytes and in vivo for the control of recurrent herpes genitalis in guinea pigs. Our results show that the liposome-antigen-adjuvant preparation is capable of enhancing antigen-specific lymphocyte stimulation, which may be related to the observed 75% suppression of the frequency and severity of reactivation of recurrent herpes simplex virus type 2 genitalis compared with that of placebo controls.

    View details for Web of Science ID A1989AA63700010

    View details for PubMedID 2542605

  • EVALUATION OF THE ANTIVIRAL EFFECT OF RIFABUTIN IN AIDS-RELATED COMPLEX JOURNAL OF INFECTIOUS DISEASES TORSETH, J., Bhatia, G., Harkonen, S., Child, C., SKINNER, M., Robinson, W. S., Blaschke, T. F., Merigan, T. C. 1989; 159 (6): 1115-1118

    View details for Web of Science ID A1989U854200018

    View details for PubMedID 2542419

  • THE HUMAN CYTOMEGALO-VIRUS STRAIN TOWNE GLYCOPROTEIN-H GENE ENCODES GLYCOPROTEIN P86 VIROLOGY PACHL, C., Probert, W. S., HERMSEN, K. M., Masiarz, F. R., Rasmussen, L., Merigan, T. C., Spaete, R. R. 1989; 169 (2): 418-426

    Abstract

    The gene encoding the glycoprotein H (gH) homologue of CMV strain Towne was cloned, sequenced, and expressed. The predicted 742 amino acid gH protein had characteristics typical of a membrane glycoprotein including hydrophobic signal and transmembrane domains and six possible N-linked glycosylation sites. The CMV (Towne) gH gene had a 95% nucleotide identity and a 96.6% amino acid identity with the CMV (AD169) gH gene, as described by M. P. Cranage, G. L. Smith, S. E. Bell, H. Hart, C. Brown, A. T. Bankier, P. Tomlinson, B. G. Barrell, and T. C. Minson (1988, J. Virol. 62, 1416-1422). Transcriptional analysis of the gH gene revealed that the 2.9-kilobase (kb) gH transcript was not detected until late after CMV infection, indicating that the kinetics of gH expression were typical of the late class of CMV genes. The gH gene was expressed in COS cells using a vector in which transcription was driven by the SV40 early promoter. The expression of gH was detected by immunofluorescence using the virus neutralizing murine monoclonal antibody 1G6, which is specific for an 86-kilodalton (kDa) CMV virion membrane protein (p86). Amino acid sequence analysis of p86 tryptic peptides revealed sequence identity with peptides from the deduced gH amino acid sequence, confirming that the gH gene encodes p86. These results indicate that CMV gH can induce virus neutralizing antibodies and establishes gH as a candidate antigen for a subunit vaccine against CMV.

    View details for Web of Science ID A1989U031000018

    View details for PubMedID 2539698

  • A PERSONAL VIEW OF EFFORTS IN TREATMENT OF HUMAN IMMUNODEFICIENCY VIRUS-INFECTION IN 1988 JOURNAL OF INFECTIOUS DISEASES Merigan, T. C. 1989; 159 (3): 390-399

    Abstract

    This presentation summarizes the US national cooperative trials for AIDS treatment and some specific efforts in the treatment of viral infections. The underlying principles behind clinical efforts in the control of the human immunodeficiency virus are described to date. In addition, concerns are voiced regarding the oversimplification of treatment issues presented in the public policy area; some will clearly require responses from interested and informed clinical scientists.

    View details for Web of Science ID A1989T266800004

    View details for PubMedID 2644377

  • TREATMENT OF B-CELL LYMPHOMAS WITH ANTI-IDIOTYPE ANTIBODIES ALONE AND IN COMBINATION WITH ALPHA INTERFERON BLOOD Brown, S. L., MILLER, R. A., Horning, S. J., Czerwinski, D., Hart, S. M., MCELDERRY, R., BASHAM, T., Warnke, R. A., Merigan, T. C., Levy, R. 1989; 73 (3): 651-661

    Abstract

    Idiotypes are distinct clonal markers for B-cell lymphomas. Previously we reported the use of anti-idiotype antibodies in the therapy of patients with B-cell malignancies. Because synergy was demonstrated with the addition of alpha interferon to anti-idiotype antibodies in a murine lymphoma model, we performed a clinical trial combining these two agents. Here we provide an update of the original trial of anti-idiotype antibodies alone and report the outcome of the new combination trial. In 16 treatment courses of anti-idiotype antibodies alone there were seven partial responses and one complete response. In 12 courses of combination anti-idiotype antibody and alpha interferon there were two complete responses and seven partial responses. Substantial tumor regressions occurred with minimal toxicity in both trials even in patients refractory to conventional chemotherapy. Tumor specimens obtained at the time of disease progression often contained a preponderance of idiotype-negative lymphoma cells, suggesting that anti-idiotype antibody treatment exerted a strong antitumor effect against antigen-positive cells. Anti-idiotype antibodies have reproducible objective antitumor activity in B-cell lymphoma. The addition of alpha interferon may improve the initial rate of response to this treatment. Strategies that deal effectively with idiotype-negative lymphoma cells should improve the extent and duration of these responses.

    View details for Web of Science ID A1989T250100006

    View details for PubMedID 2465039

  • CIRCULATING P24 ANTIGEN LEVELS AND RESPONSES TO DIDEOXYCYTIDINE IN HUMAN IMMUNODEFICIENCY VIRUS (HIV) INFECTIONS - A PHASE-I AND PHASE-II STUDY ANNALS OF INTERNAL MEDICINE Merigan, T. C., Skowron, G., Bozzette, S. A., Richman, D., UTTAMCHANDANI, R., Fischl, M., SCHOOLEY, R., Hirsch, M., SOO, W., Pettinelli, C., Schaumburg, H. 1989; 110 (3): 189-194

    Abstract

    To determine the safety and efficacy of dideoxycytidine in patients with the acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex.A partially randomized phase I and II outpatient, dose-ranging study.Four university medical centers involving government-supported referral AIDS Clinical Trial Units.Sixty-one patients with AIDS or advanced AIDS-related complex and 100 pg/mL or more serum p24 antigen titers.Dideoxycytidine was administered orally at 0.06, 0.03, 0.01, or 0.005 mg/kg body weight every 4 hours for 3 to 6 months depending on tolerance and benefit.In patients receiving 0.06 and 0.03 mg/kg, diffuse erythematous rash, fever, and aphthous stomatitis occurred in the first weeks of therapy, but resolved later. Hematopoietic suppression was rare. Peripheral sensory neuropathy occurred in patients receiving 0.06 mg/kg and 0.03 mg/kg and improved after discontinuation of therapy. Serum p24 antigen fell significantly (P less than 0.01) from baseline entry values in most of these patients. The CD4 lymphocytes rose transiently at the 0.03 mg/kg dosage. At the 0.005 mg/kg dosage, skin rash, fever, and aphthous stomatitis were mild or absent. Peripheral neuropathy, which occurred in all patients receiving 0.01 mg/kg was less severe than at higher dosages. At the 0.005 mg/kg dosage, peripheral neuropathy was occasionally seen. Significant suppression of serum p24 antigen was seen in most patients with AIDS-related complex receiving 0.01 mg/kg and less frequently in patients receiving 0.005 mg/kg.Less toxic regimens of dideoxycytidine merit clinical assessment for advanced anti-human immunodeficiency virus-1 (HIV) infection. Several studies alternating dideoxycytidine and zidovudine are in progress.

    View details for Web of Science ID A1989T106000004

    View details for PubMedID 2536257

  • HUMAN CYTOMEGALO-VIRUS STRAIN TOWNE GLYCOPROTEIN-B IS PROCESSED BY PROTEOLYTIC CLEAVAGE VIROLOGY Spaete, R. R., THAYER, R. M., Probert, W. S., Masiarz, F. R., CHAMBERLAIN, S. H., Rasmussen, L., Merigan, T. C., PACHL, C. 1988; 167 (1): 207-225

    Abstract

    The gene encoding glycoprotein B of human cytomegalovirus (CMV) strain Towne was cloned, sequenced, and expressed in order to study potential targets for viral neutralization. Secondary structure analysis of the 907 amino acid protein predicted a 24 amino acid N-terminal signal sequence and a potential transmembrane region composed of two domains, 34 and 21 amino acids. The CMV (Towne) gB gene had a 94% nucleotide similarity and a 95% amino acid similarity to the CMV (AD169) gB gene [as described by M.P. Cranage et al. (1986, EMBO J. 5, 3057-3063)]. Transcriptional analysis of the CMV (Towne) gB coding strand revealed that the gB message (3.9 kb), was transcribed from this region as early as 4 hr postinfection, and well in advance of gB protein synthesis. Full-length and truncated versions of the gB gene were expressed in COS cells using expression vectors where transcription was driven by the SV40 early promoter or the CMV major immediate early promoter. Expression was detected by immunofluorescence and ELISA using the virus neutralizing murine monoclonal antibody 15D8 (L. Rasmussen, J. Mullenax, R. Nelson, and T.C. Merigan, 1985, J. Virol. 55, 274-280). This antibody had been shown previously to recognize a 55-kDa CMV virion protein and a related 130-kDa intracellular precursor. Amino acid sequence analysis of the N-terminus of the 55-kDa viral glycoprotein (gp55) showed that gp55 is derived from gB (gp130) by proteolytic cleavage and represents the C-terminal region of gp130. The truncated version of gB expressed in COS and CHO cells was also processed by proteolytic cleavage as demonstrated by Western blotting. Our study localizes the epitope recognized by 15D8 to within a 186 amino acid fragment of the gp55 protein. These results indicate that CMV gB is a target for neutralization and establishes gp55 as a candidate component for use in a subunit vaccine.

    View details for Web of Science ID A1988Q895500025

    View details for PubMedID 2460994

  • TOPICAL INTERFERON FOR TREATING CONDYLOMA ACUMINATA IN WOMEN JOURNAL OF INFECTIOUS DISEASES Keay, S., Teng, N., Eisenberg, M., Story, B., SELLERS, P. W., Merigan, T. C. 1988; 158 (5): 934-939

    Abstract

    We conducted a randomized, double-blind, placebo-controlled trial of two forms of topical interferon therapy for condyloma acuminata in women. Gel containing 10(6) IU of leukocyte interferon/g, with or without nonoxynol-9, was compared with treatment with gel base alone. Eighty-nine patients applied the gel three times a day for four weeks and were studied for at least 16 w. Side effects were generally mild and limited to the site of application for all three drugs. Although a transient, statistically significant therapeutic effect was noted early in the course of treatment with both interferon gels as compared with placebo, this effect was lost by the end of the follow-up period, possibly because of a generally high response rate in patients receiving placebo. Hence, there was no overall difference in the number of patients with a partial or complete response to any of the agents by the end of therapy or by the end of the study.

    View details for Web of Science ID A1988Q700100004

    View details for PubMedID 2460568

  • SYNERGISTIC ANTITUMOR-ACTIVITY WITH IFN AND MONOCLONAL ANTI-IDIOTYPE FOR MURINE B-CELL LYMPHOMA - MECHANISM OF ACTION JOURNAL OF IMMUNOLOGY BASHAM, T. Y., RACE, E. R., Campbell, M. J., Reid, T. R., Levy, R., Merigan, T. C. 1988; 141 (8): 2855-2860

    Abstract

    Combination therapy with syngeneic anti-idiotype antibody and human hybrid rIFN-alpha A/D synergistically increase survival in C3H/HeN mice challenged with a lethal dose of tumor cells. C3H/HeJ mice, which have previously been described to be LPS hyporesponsive and have a defect in Fc gamma R function, did not respond to anti-idiotype therapy as well as C3H/HeN normal mice. This defect was completely corrected in animals treated simultaneously with IFN. Anti-idiotype mAb that was cleaved into F(ab')2 fragments no longer had any antitumor activity alone and could not be enhanced by IFN therapy. These results suggest that antibody is functioning through Fc gamma R-bearing effector cells that are enhanced by IFN therapy. Synergy between IFN and anti-idiotype mAb was maintained in nude mice lacking classical T cells but was reduced in C3H beige mice lacking classical NK/killer cells. IFN did not increase idiotype expression on the tumor cells but did increase H-2 expression. Although we have previously shown that rIFN-alpha A/D can directly kill 38C13 in vitro, an IFN-resistant subclone derived from 38C13, SIR-1, was equally or more responsive to human rIFN-alpha A/D in vivo and had a synergistic antitumor response to combination IFN and anti-idiotype therapy, indicating that IFN acts primarily through host mediated effects rather than direct effects.

    View details for Web of Science ID A1988Q342300052

    View details for PubMedID 2971732

  • COMPARISON OF COMBINATIONS OF INTERFERONS WITH TUMOR SPECIFIC AND NONSPECIFIC MONOCLONAL-ANTIBODIES AS THERAPY FOR MURINE B-CELL AND T-CELL LYMPHOMAS CANCER RESEARCH BASHAM, T. Y., Palladino, M. A., BADGER, C. C., Bernstein, I. D., Levy, R., Merigan, T. C. 1988; 48 (15): 4196-4200

    Abstract

    Two murine models, C3H 38C13 B-cell lymphoma and AKR SL2 T-cell lymphoma were used to determine the efficacy of three different interferon preparations, recombinant human hybrid interferon-alpha A/D, recombinant murine interferon (rMIFN)-gamma, and natural MIFN-alpha/beta (greater than or equal to 85% beta), alone and in combination with tumor specific and nonspecific monoclonal antibody therapy. All three interferon preparations have direct in vitro antigrowth activity for 38C13 and SL2. All three interferons have direct antitumor activity in vivo for 38C13 lymphoma at high doses; however, none of these interferons has independent antitumor activity for SL2 in vivo. These data indicate that there is no relationship between in vitro growth cytostasis/cytolysis and in vivo antitumor response. All three interferon preparations will potentiate both tumor specific and nonspecific monoclonal antibody therapy. Natural MIFN-alpha/beta and recombinant human hybrid interferon-alpha A/D, which should share a common cell surface receptor, had similar antitumor activity in both models. Combining recombinant human hybrid interferon-alpha A/D and rMIFN-gamma therapy was not additive for 38C13 lymphoma and a three-way combination with antiidiotype was not significantly more effective than combination therapy with one interferon type. In general, rMIFN-gamma was more effective in in vivo combination therapy against the s.c. T-cell lymphoma than against the i.p. B-cell lymphoma and was more synergistic with anti-Thy1.1 than with antiidiotype.

    View details for Web of Science ID A1988P330500011

    View details for PubMedID 2455592

  • GANCICLOVIR TREATMENT OF SERIOUS CYTOMEGALO-VIRUS INFECTION IN HEART AND HEART-LUNG TRANSPLANT RECIPIENTS REVIEWS OF INFECTIOUS DISEASES Keay, S., Petersen, E., Icenogle, T., ZELUFF, B. J., SAMO, T., Busch, D., Newman, C. L., Buhles, W. C., Merigan, T. C. 1988; 10: S563-S572

    Abstract

    Experience with ganciclovir treatment of life- or sight-threatening cytomegalovirus (CMV) infections in 22 heart and heart-lung transplant recipients at six medical centers was reviewed. All six heart-lung recipients and six of 16 heart recipients had CMV pneumonitis; five heart recipients had CMV gastrointestinal disease, three had retinitis, and two had infections in more than one organ system. Of the 18 patients (82%) surviving initial ganciclovir therapy, 16 improved, one stabilized, and one showed no change in clinical status. All cultures positive for CMV before treatment became negative during therapy. Six patients (33% of survivors) had recurrent episodes and received additional therapy. Four patients (18%) died during initial therapy; death was believed to be related to CMV infection in only two cases and to ganciclovir treatment in no case. Adverse reactions possibly attributable to ganciclovir included neutropenia (four patients), impaired renal function (one), thrombocytopenia (one), decreased blood pressure (one), and seizure (one). Ganciclovir appears to be well tolerated and to alter favorably the outcome of serious CMV infection in this patient population.

    View details for Web of Science ID A1988P724600014

    View details for PubMedID 2847294

  • HUMAN INTERFERON AS A THERAPEUTIC AGENT - A DECADE PASSES NEW ENGLAND JOURNAL OF MEDICINE Merigan, T. C. 1988; 318 (22): 1458-1460

    View details for Web of Science ID A1988N594000008

    View details for PubMedID 2452984

  • RECOMBINANT FIBROBLAST INTERFERON AND IMMUNE INTERFERON FOR TREATING CHRONIC HEPATITIS-B VIRUS-INFECTION - PATIENTS TOLERANCE AND THE EFFECT ON VIRAL MARKERS JOURNAL OF INFECTIOUS DISEASES Bissett, J., Eisenberg, M., Gregory, P., Robinson, W. S., Merigan, T. C. 1988; 157 (5): 1076-1080

    View details for Web of Science ID A1988N048100036

    View details for PubMedID 3129521

  • CHARACTERIZATION OF 2 DIFFERENT HUMAN CYTOMEGALO-VIRUS GLYCOPROTEINS WHICH ARE TARGETS FOR VIRUS NEUTRALIZING ANTIBODY VIROLOGY Rasmussen, L., Nelson, M., Neff, M., Merigan, T. C. 1988; 163 (2): 308-318

    Abstract

    In previous studies we have identified two viral polypeptides detected by murine monoclonal antibodies which neutralize the infectivity of human cytomegalovirus (CMV) AD169. One is an 86,000-Da polypeptide (p86) and the second is a complex of two major coimmunoprecipitating polypeptides of 130,000 and 55,000 Da (p130/55). In this study we have shown that the two viral polypeptides are immunologically unrelated and have distinct peptide cleavage patterns. We have characterized these polypeptides as glycoproteins and studied their biosynthesis in human embryonic lung cells. The oligosaccharides found on both the p86 and the p130/55 were characterized by endoglycosidase digestion as N-linked high-mannose carbohydrates. Inhibitors of glycosylation were used to further characterize the oligosaccharides. Tunicamycin, which inhibits the biosynthesis of N-linked oligosaccharides on the endoplasmic reticulum, inhibited both the infectivity and biosynthesis of the p86 and p130/55. The underglycosylated forms in tunicamycin-treated cultures could be detected only under conditions of pulse-labeling with L-[35S]methionine. Monensin, which inhibits the modification of glycoproteins from simple to complex forms in the Golgi, reduced viral infectivity at concentrations which had no effect on viral protein synthesis, but did not alter the apparent molecular weight of either the p86 or the p130/55. The oligosaccharides were critical for the in vitro immunologic reactivity of the p86 in immunoblots. However, endoglycosidase F-treated p86 was comparable to the native form in inducing virus neutralizing antibody in guinea pigs. Endoglycosidase F-treated p130/55 retained its ability to bind antibody in Western blots.

    View details for Web of Science ID A1988M825100007

    View details for PubMedID 2833009

  • RECOMBINANT HIV STRUCTURAL PROTEINS DETECT SPECIFIC CELLULAR-IMMUNITY INVITRO IN INFECTED INDIVIDUALS AIDS RESEARCH AND HUMAN RETROVIRUSES Torseth, J. W., Berman, P. W., Merigan, T. C. 1988; 4 (1): 23-30

    Abstract

    Peripheral blood mononuclear cell (PBMC) cultures were established from patients with antibody to human immunodeficiency virus (HIV). Asymptomatically infected patients [5 of 19] had significant lymphocyte transformation responses induced in culture by a purified, recombinant envelope glycoprotein (rgp120) from the virus. A few (4 of 55) subjects with AIDS related complex (ARC) and no subjects with AIDS (0 of 29) had proliferative responses to this protein. These responses correlated directly with circulating levels of helper/inducer lymphocytes (p less than .01) and indirectly with virus antigen in blood (p = .04). Also, these responses occurred significantly less frequently than responses to herpes simplex virus (HSV) or cytomegalovirus (CMV) antigens in seropositive ARC patients (p less than .005). These data indicate that the frequency of immune cellular responses to rgp120 decline in association with disease progression, and become undetectable in frank AIDS. As rgp120-induced proliferation was not observed in cells from 15 seronegative immunocompetent subjects, this response appears immune specific. Immune T-lymphocyte-mediated responses to this HIV envelope glycoprotein may allow the prediction of future clinical events and may be useful in monitoring immune-enhancing therapy in patients with ARC and AIDS.

    View details for Web of Science ID A1988M692500005

    View details for PubMedID 2835070

  • SYNGENEIC MONOCLONAL ANTI-IDIOTYPE ANTIBODIES THAT BEAR THE INTERNAL IMAGE OF A HUMAN CYTOMEGALO-VIRUS NEUTRALIZATION EPITOPE JOURNAL OF IMMUNOLOGY Keay, S., Rasmussen, L., Merigan, T. C. 1988; 140 (3): 944-948

    Abstract

    Two glycoproteins have been identified on human CMV that induce neutralizing antibody; an 86,000-Da glycoprotein and a 130,000-, 92,000-, and 50,000-Da glycoprotein coimmunoprecipitating complex that appears to be the gB homologue of HSV. We have produced syngeneic monoclonal anti-Id antibodies (mAb2) of the IgM isotype to a CMV-neutralizing monoclonal antibody (mAb1) that is known to bind to the 86,000-Da glycoprotein on the virion envelope. These mAb2 bear the internal image of the original viral antigen as shown by their ability to 1) recognize an interspecies idiotype in CMV-positive human antisera, 2) block mAb1 binding to CMV antigen, and 3) block CMV neutralization by mAb1 in vitro. Immunization of mice with both of these affinity chromatography-purified mAb2 stimulated the production of anti-anti-Id monoclonal antibodies (which we termed mAb3), which bound to the mAb2 by ELISA and neutralized CMV infectivity.

    View details for Web of Science ID A1988M021200042

    View details for PubMedID 2448380

  • Viral diseases in developing countries. APMIS. Supplementum Merigan, T. C. 1988; 3: 26-29

    View details for PubMedID 3052534

  • RECOMBINANT INTERLEUKIN-2 AS AN ADJUVANT FOR VACCINE-INDUCED PROTECTION - IMMUNIZATION OF GUINEA-PIGS WITH HERPES-SIMPLEX VIRUS SUBUNIT VACCINES JOURNAL OF IMMUNOLOGY Weinberg, A., Merigan, T. C. 1988; 140 (1): 294-299

    Abstract

    We determined that recombinant interleukin 2 (rIL-2) administered in conjunction with herpes simplex virus (HSV) crude extract or recombinant glycoprotein D subunit vaccine enhances the protective effect of either antigen preparation against HSV type 2 genital infection in guinea pigs. Animals that received the vaccine accompanied by rIL-2 had an incidence of infection, assessed by detection of clinical lesions and/or viral shedding, that varied between 0 and 43% significantly lower than the incidence of 63 to 100% in guinea pigs submitted to the same immunization schedule without rIL-2. Animals that escaped acute infection failed to develop recurrent disease. In addition, severity of acute infection was decreased by rIL-2 co-administration as well as by increasing the number of vaccine doses. We also studied the immune response of the guinea pigs to vaccination and the mechanism of protection. Both enzyme-linked immunosorbent assay titers of antibodies to HSV type 2 and specific antigen stimulation of lymphocytes measured by proliferation and interferon production did not significantly differ among the immunization groups. However, specific cellular cytotoxicity was enhanced by rIL-2 co-administration and was positively correlated with protection. This suggests that rIL-2 may become an important adjuvant in active immunization programs using subunit vaccines, particularly against diseases in which cellular cytotoxicity is a major defense mechanism.

    View details for Web of Science ID A1988L504600046

    View details for PubMedID 2826591

  • GANCICLOVIR TREATMENT OF CYTOMEGALOVIRUS INFECTIONS IN IATROGENICALLY IMMUNOCOMPROMISED PATIENTS JOURNAL OF INFECTIOUS DISEASES Keay, S., Bissett, J., Merigan, T. C. 1987; 156 (6): 1016-1021

    View details for Web of Science ID A1987K857100028

    View details for PubMedID 2824621

  • IS RECOMBINANT INTERLEUKIN-2 THE BEST WAY TO DELIVER INTERFERON-GAMMA IN HUMAN-DISEASE JOURNAL OF INTERFERON RESEARCH Merigan, T. C. 1987; 7 (5): 635-639

    Abstract

    Studies in man have suggested that interferon-gamma (IFN-gamma)-producing T cells are important in herpes simplex disease recurrences. These have led to the use of interleukin-2 (IL-2) in a guinea pig model of herpes simplex genital infection. Here, that lymphokine lessens the severity of acute and chronic herpes simplex disease and it also produces an adjuvant action on the protective effect of herpes simplex virus (HSV) subunit vaccines. A variety of potentially useful actions of IL-2 might underly these effects, including increased lymphokine release and enhanced cytotoxic actions of natural killer, lymphokine-activated killer cells, or histocompatibility antigen restricted T cells. IL-2 appears to be involved in the mobilization of IFN-gamma-producing T lymphocytes, which may mediate the enhancement of the previously mentioned immune functions. It seems appropriate to explore these effects of IL-2 in human viral disease. Since the systemic use of IFN-gamma is limited by side effects, IL-2 may be an important mechanism for physiologic delivery of IFN-gamma to local sites.

    View details for Web of Science ID A1987K545000034

    View details for PubMedID 3119733

  • ASSESSMENT OF THE ANTIGENIC RESPONSE IN HUMANS TO A RECOMBINANT MUTANT INTERFERON-BETA JOURNAL OF CLINICAL IMMUNOLOGY KONRAD, M. W., Childs, A. L., Merigan, T. C., Borden, E. C. 1987; 7 (5): 365-375

    Abstract

    Cancer patients were given a recombinant mutant interferon beta by alternating IM and IV injections with weekly escalation of doses from 0.1 to 400 million U. Antibodies specific to the interferon of the IgG class were detected in 24 of 30 patients using an indirect enzyme-linked immunosorbent assay. Serum from only 1 of the 30 patients had detectable ability to neutralize interferon biological activity. The in vivo interferon serum level, assayed as antiviral activity immediately after IV injection, was not lower than levels seen in the absence of antibodies. Antibodies did not alter the kinetics of clearance of interferon from the serum after IV administration. Antibody levels progressively decreased when interferon administration was discontinued. In most patients antibody levels decreased during a maintenance period when interferon was being administered only by the IV route. In a subsequent trial interferon was given IV, and antibody developed in only 2 of 36 patients. In contrast, in a trial in which interferon was given IM, 20 of 25 patients developed antibody. No antibody-related clinical sequelae could be detected in any of these patients.

    View details for Web of Science ID A1987J891700003

    View details for PubMedID 3308943

  • REGULATION BY RECOMBINANT INTERLEUKIN-2 OF PROTECTIVE IMMUNITY AGAINST RECURRENT HERPES-SIMPLEX VIRUS TYPE-2 GENITAL-INFECTION IN GUINEA-PIGS JOURNAL OF VIROLOGY Weinberg, A., Konrad, M., Merigan, T. C. 1987; 61 (7): 2120-2127

    Abstract

    The goal of our study was to determine whether recombinant interleukin-2 (rIL-2) could modify the recurrence pattern of chronic herpes simplex virus type 2 (HSV-2) genital infection in guinea pigs. Animals that developed symptomatic acute HSV-2 infection were distributed at 14 days after viral inoculation into several treatment groups, which were similar with respect to the severity of acute disease. Three rIL-2 dosages administered for 4 weeks in daily subcutaneous injections were tested in this study: 5 X 10(3), 5 X 10(4), and 2.5 X 10(5) U. Daily observations of the animals showed a significant decrease of the incidence of new recurrent lesions with the use of 5 X 10(4) U of rIL-2 (rate of recurrence, 0.08, compared with 0.21 in untreated controls), whereas the other rIL-2 regimens did not affect the overall rate of recurrence. Weekly analysis of recurrences showed that treatment with 5 X 10(4) U of rIL-2 was effective only during the first 3 weeks of use and that 2.5 X 10(5) U of rIL-2 markedly decreased the rate of recurrence in the first week of treatment but not in subsequent weeks. The loss of clinical protection in both groups coincided with the production of neutralizing antibodies to rIL-2. The immune mechanisms possibly involved in the protective effect of rIL-2 in chronic HSV-2 disease were further investigated. Production of gamma interferon correlated well with clinical protection, and circulating levels dropped at the time when neutralizing antibodies to rIL-2 developed. Nonspecific cytotoxicity represented by natural killer cell and lymphokine-activated killer cell activities was also increased in the treated guinea pigs. Antibody titers and lymphocyte proliferation to herpes simplex antigen were similar in rIL-2 and placebo recipients. Finally, we found that the rIL-2-induced immune stimulation was as protective against recurrent HSV-2 disease in guinea pigs as the viral suppression achieved with acyclovir. However, the biological activity of both drugs was not additive when they were coadministered.

    View details for Web of Science ID A1987H645600008

    View details for PubMedID 3035213

  • NATIVE AND RECOMBINANT HERPES-SIMPLEX VIRUS TYPE-1 ENVELOPE PROTEINS INDUCE HUMAN IMMUNE LYMPHOCYTE-T RESPONSES JOURNAL OF VIROLOGY Torseth, J. W., Cohen, G. H., Eisenberg, R. J., Berman, P. W., LASKY, L. A., CERINI, C. P., Heilman, C. J., Kerwar, S., Merigan, T. C. 1987; 61 (5): 1532-1539

    Abstract

    The abilities of whole herpes simplex virus type 1 (HSV-1) antigen (HSV-ag) and purified HSV-1 native and recombinant envelope proteins to stimulate in vitro T-lymphocyte responses were compared in patients with recurrent herpes labialis. Immunochemically purified preparations of native glycoproteins B, C, and D (ngB, ngC, ngD) from cultured HSV-1 as well as expressed recombinant plasmid preparations of gD (rgD-1t, rgD-45K) elicited lymphocyte proliferation (LT) and production of gamma interferon (IFN-gamma) and interleukin-2 (IL-2) only in seropositive individuals. The IFN-gamma induced by rgD-1t correlated with the time to the next herpetic lesion in 19 volunteers followed to recurrence (r = 0.69, P less than 0.008), although the magnitude and frequency of LT and IFN-gamma responses were lower with either recombinant or native purified antigens than with the whole-virus antigen. Combinations of ngB plus ngD or ngB plus ngC plus ngD stimulated more IFN-gamma, equivalent to whole-virus-antigen responses. Recombinant-derived human IL-2 also specifically increased LT and IFN-gamma responses in antigen-driven cultures. ngD stimulated IL-2 and LT responses similar to those of whole-virus antigen and higher than those of ngC. HSV-ag and ngB induced significantly higher titers of total IFN than could be accounted for by IFN-gamma; this was not seen for the other antigens, which induced only IFN-gamma. HSV-ag-driven Leu 2a-, plastic-nonadherent blood cells, unlike whole peripheral blood mononuclear cells, showed evidence of an increase and then a decline in the frequency of HSV-responsive cells after a lesion recurrence. These studies suggest that HSV-1 envelope proteins are capable of stimulating an immune T-helper-cell response which is associated with the prevention of human herpes simplex lesion recurrence. Although the whole virus probably contains additional important antigens, increasing concentrations or combinations of certain purified glycoproteins or the addition of nonspecific enhancers of T-lymphocyte function can drive in vitro immune responses to the same level as the complete set of viral antigens.

    View details for Web of Science ID A1987G923200030

    View details for PubMedID 3033279

  • INTERFERON-BETA PRODUCED BY KERATINOCYTES IN HUMAN CUTANEOUS INFECTION WITH HERPES-SIMPLEX VIRUS JOURNAL OF INFECTIOUS DISEASES Torseth, J. W., Nickoloff, B. J., BASHAM, T. Y., Merigan, T. C. 1987; 155 (4): 641-648

    Abstract

    beta Interferon (IFN) was demonstrated by specific, sequential antibody-neutralization assays of vesicle fluids from patients with recurrent skin lesions due to herpes simplex virus. To determine the origin of this antiviral activity, we cultured keratinocytes from normal facial skin and infected them with three strains of herpes simplex virus. Keratinocyte cultures then developed characteristic cytopathic changes, and antiviral activity was found in culture supernatant media. All such activity from these supernatants was neutralized with specific antiserum to IFN-beta but not with antiserum to IFN-alpha. No IFN-gamma was detectable by radioimmunoassay. Immunoperoxidase staining with antiserum to IFN-beta in five biopsy specimens from culture-proven, recurrent herpes simplex lesions showed positive staining of epidermal keratinocytes but not of dermal or infiltrating cells. Thus, the primary sources of IFN-beta in recurrent herpes lesion vesicles are the virus-infected keratinocytes.

    View details for Web of Science ID A1987G368200008

    View details for PubMedID 2434580

  • REGULATION OF GUINEA-PIG IMMUNE FUNCTIONS BY INTERLEUKIN-2 - CRITICAL ROLE OF NATURAL-KILLER ACTIVITY IN ACUTE HSV-2 GENITAL-INFECTION JOURNAL OF IMMUNOLOGY Weinberg, A., BASHAM, T. Y., Merigan, T. C. 1986; 137 (10): 3310-3317

    Abstract

    We have previously demonstrated that recombinant interleukin 2 (rIL 2) has a protective effect against acute HSV-2 infection in guinea pigs with a biphasic dose response which peaked between 4 and 20 X 10(4) U/kg, whereas 8 X 10(5) U/kg showed no effect on disease. Animals that escaped infection appeared lack immunologic memory to HSV-2, suggesting a nonspecific immune mechanism. In this study we have found that NK activity of fresh splenocytes measured against HSV-2 infected human foreskin fibroblast (HFF) is stimulated in vitro and in vivo by rIL 2 in a biphasic dose range similar to that determined for protection against disease. In contrast, lymphokine-activated killer (LAK)-mediated lysis of P815 showed a linear response to increasing concentrations of rIL 2 both in vitro and in vivo. Transfer of LAK cells did not alter the rate of infection after HSV-2 challenge. Anti-asialo GM-1 eliminated rIL 2 protection against HSV-2 infection. It also blocked HSV-2/HFF lysis and partially decreased P815 lysis in vitro; however, in vivo it inhibited both natural killer (NK) activity and LAK generation, failing to distinguish which of the lytic cells was responsible for the effect against infection. Early IgG production (7 days post-infection) was enhanced by rIL 2 administration before viral inoculation, but it did not influence the rate of infection as compared with controls. Polyclonal IgM secretion was not found to play a role in acute protection. Circulating serum interferon levels were enhanced with increasing concentrations of rIL 2 but did not correlate with the biphasic dose curve for protection. Therefore of these mechanisms the one that is most closely related to the protective effect of rIL 2 against primary HSV-2 infection appears to be NK-mediated lysis, although the other mechanisms may add to this effect.

    View details for Web of Science ID A1986E709400042

    View details for PubMedID 3021853

  • SYNERGISTIC ANTITUMOR EFFECT OF INTERFERON AND ANTIIDIOTYPE MONOCLONAL-ANTIBODY IN MURINE LYMPHOMA JOURNAL OF IMMUNOLOGY BASHAM, T. Y., Kaminski, M. S., Kitamura, K., Levy, R., Merigan, T. C. 1986; 137 (9): 3019-3024

    Abstract

    Both IFN-alpha and anti-idiotype monoclonal antibody therapy have significant antitumor activity in vivo in a murine B cell lymphoma model. Combination therapy with syngeneic anti-idiotype antibody of the IgG2a or IgG2b isotype (a single i.p. injection of 100 micrograms) and recombinant human hybrid interferon-alpha A/D (10(4) to 10(6) U three times weekly for 3 wk) synergistically increased median survival time in mice challenged with a lethal dose of tumor cells compared with the sum of the median survival times of the two individual treatments. IFN-alpha has direct antiproliferative activity against 38C13 in vitro and enhances in vitro macrophage anti-idiotype antibody-specific cytolysis for IgG2a, IgG2b, and IgG1 isotypes.

    View details for Web of Science ID A1986E489100046

    View details for PubMedID 3760580

  • HUMAN KERATINOCYTE-LYMPHOCYTE REACTIONS INVITRO JOURNAL OF INVESTIGATIVE DERMATOLOGY Nickoloff, B. J., BASHAM, T. Y., Merigan, T. C., Torseth, J. W., Morhenn, V. B. 1986; 87 (1): 11-18

    Abstract

    To extend our observation that recombinant gamma interferon (r-IFN-gamma) induces the synthesis and expression of HLA-DR antigen we have investigated 2 major areas including the modulation of r-IFN-gamma-induced HLA-DR expression and the possible immunologic consequences of keratinocyte HLA-DR expression in vitro. The induction of keratinocyte HLA-DR expression was greater for continuous compared with pulse dosage (0.5-24 h) of r-IFN-gamma and was markedly decreased after trypsinization of attached monolayers into single cell suspensions. The r-IFN-gamma caused induction of HLA-DR and this was not influenced by either pretreatment with irradiation, PGE2, or indomethacin. Both HLA-DR+ and HLA-DR- cultured keratinocytes induced RNA synthesis and gamma interferon production by allogeneic peripheral blood mononuclear leukocytes (PBMLs) indicating mononuclear cell activation. However, this activation was not followed by significant mitogenesis and only slightly increased levels of [3H]thymidine incorporation (maximal = 5800 cpm) by the PBMLs was observed. Cultured keratinocytes apparently inhibit both lectin-driven and mixed-lymphocyte reactions by producing a soluble mediator which is not dialyzable, or inhibited by pretreatment with indomethacin or anti-alpha, -beta, -gamma interferon antibodies. These results suggest that lymphocyte-keratinocyte reactions in vitro are complex and may be mediated by a variety of cytokines, lymphokines, and prostaglandins.

    View details for Web of Science ID A1986D111400006

    View details for PubMedID 2941488

  • ACUTE GENITAL-INFECTION IN GUINEA-PIGS - EFFECT OF RECOMBINANT INTERLEUKIN-2 ON HERPES-SIMPLEX VIRUS TYPE-2 JOURNAL OF INFECTIOUS DISEASES Weinberg, A., Rasmussen, L., Merigan, T. C. 1986; 154 (1): 134-140

    Abstract

    Human recombinant interleukin-2 (rIL-2) modifies infection with herpes simplex virus type 2 (HSV-2) in normal guinea pigs. Animals were injected sc with rIL-2 twice a day, beginning 24 hr before infection and continuing for three subsequent days. Guinea pigs were assigned to five different regimens in which rIL-2 was administered daily at dosages from 8 X 10(3) U/kg to 8 X 10(5) U/kg. After intravaginal inoculation with HSV-2, 83% of 24 control animals developed apparent genital herpes, and 5% had asymptomatic viral shedding. Animals receiving 4 X 10(4) U or 2 X 10(5) U or rIL-2/kg showed a significantly lower rate of infection (P less than .001 by chi 2) and a lower number of lesions and more rapid healing than did the infected animals in the control (untreated) group. The mortality in the untreated group (28%) was higher than in the animals in the 2 X 10(5) U/kg treatment group (7%). No difference was observed between the control, the 8 X 10(3) U/kg, and the 8 X 10(5) U/kg treatment groups with respect to severity of infection or mortality. Animals examined two to four weeks after inoculation had lymphocyte stimulation indices (induced with HSV-2 antigen) greater than 3.5 and titers of antibody between 2.5 log10 and 4.5 log10 by radioimmunoassay. In the disease-free animals, stimulation indexes were less than 2 and antibodies were undetectable. The mean stimulation index was 54 +/- 16 in the diseased control animals and 12 +/- 7 (P less than .05) in the 2 X 10(5) U/kg treatment group.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1986C823200017

    View details for PubMedID 3011918

  • SIGNIFICANCE OF LOCAL GAMMA-INTERFERON IN RECURRENT HERPES-SIMPLEX INFECTION JOURNAL OF INFECTIOUS DISEASES Torseth, J. W., Merigan, T. C. 1986; 153 (5): 979-984

    View details for Web of Science ID A1986C110800024

    View details for PubMedID 3084668

  • CERVICAL INTRAEPITHELIAL NEOPLASIA TREATED BY PERILESIONAL INJECTION OF INTERFERON BRITISH JOURNAL OF OBSTETRICS AND GYNAECOLOGY CHOO, Y. C., Seto, W. H., Hsu, C., Merigan, T. C., Tan, Y. H., Ma, H. K., NG, M. H. 1986; 93 (4): 372-379

    Abstract

    Twelve patients with cervical intraepithelial neoplasia (CIN) were studied by colposcopy and cervical smears to elucidate the local response to interferon alpha and beta given by perilesional injections and to assess long-term disease remission. In all patients, local inflammatory response was seen and persisted throughout the treatment period. Selective toxic effect was evident by exfoliation of increasing proportion of degenerate to viable dyskaryotic cells, while the normal epithelial cells appeared unaffected, and by the progressive regression of the lesion. Interferon alpha induced complete remission in six of seven (85.7%) patients but three had recurrence 12 to 24 months later, while interferon beta induced complete remission in only two of five (40%) patients.

    View details for Web of Science ID A1986C012200015

    View details for PubMedID 3964615

  • PRELIMINARY TRIAL OF RECOMBINANT FIBROBLAST INTERFERON IN CHRONIC HEPATITIS-B VIRUS-INFECTION ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Eisenberg, M., ROSNO, S., Garcia, G., KONRAD, M. W., Gregory, P. B., Robinson, W. S., Merigan, T. C. 1986; 29 (1): 122-126

    Abstract

    Five patients with chronic hepatitis B were treated with 8-day courses of leukocyte (alpha) interferon (5 X 10(6) U/day) and with 8-day courses of recombinant fibroblast (betaser) interferon at dosages of 5 X 10(6), 35 X 10(6), and 105 X 10(6) U/day. Inhibition of hepatitis B virus replication as evidenced by a decrease in DNA polymerase (DNAP) activity was seen during all treatment courses. Equivalent reduction in DNAP was seen from the low-dose alpha and beta ser regimens, but beta ser interferon at 35 X 10(6) U/day achieved a significantly greater decrease in DNAP activity than did the low-dose regimens. In no patient, however, was permanent loss of DNAP noted. Because of dose-limiting toxicity, only two patients were escalated to the 105 X 10(6)-U/day dosage level. Transient proteinuria was noted in two patients while they were receiving interferon. This has not been noted in other patients receiving this preparation and could not be explained by the development of anti-interferon antibodies. This study has defined an appropriate dosage for future longer-term trials of this agent alone and in combination with other antivirals for the treatment of chronic hepatitis B.

    View details for Web of Science ID A1986AXH3700024

    View details for PubMedID 3524420

  • SERIAL IMMUNOLOGICAL STUDIES IN MULTIPLE-SCLEROSIS PATIENTS TREATED SYSTEMICALLY WITH HUMAN ALPHA-INTERFERON ANNALS OF NEUROLOGY Panitch, H. S., Francis, G. S., Hooper, C. J., Merigan, T. C., Johnson, K. P. 1985; 18 (4): 434-438

    Abstract

    A battery of immunological functions was studied over a 2-year period in conjunction with a placebo-controlled trial of natural human alpha interferon in patients with multiple sclerosis. IgG synthesis was increased both systemically and intrathecally by administration of interferon; however, there were only minor changes in cerebrospinal fluid oligoclonal bands. Levels of helper and suppressor T lymphocytes fluctuated independently of clinical exacerbations, although mean helper/suppressor ratios were higher in multiple sclerosis patients than in controls and increased further during interferon treatment. Cerebrospinal fluid myelin basic protein and antibodies to basic protein were not affected by exacerbations or by interferon administration. Circulating IgG antibodies induced by interferon treatment appeared to be directed at a non-interferon contaminant of the preparation. None of the assays was a consistent indicator of disease activity or of clinical response to interferon.

    View details for Web of Science ID A1985AUJ5300003

    View details for PubMedID 2416265

  • RECOMBINANT GAMMA INTERFERON DIFFERENTIALLY REGULATES CLASS-II ANTIGEN EXPRESSION AND BIOSYNTHESIS ON CULTURED NORMAL HUMAN KERATINOCYTES JOURNAL OF INTERFERON RESEARCH BASHAM, T. Y., Nickoloff, B. J., Merigan, T. C., Morhenn, V. B. 1985; 5 (1): 23-32

    Abstract

    Recombinant gamma interferon induces class II antigen (HLA-DR) biosynthesis and expression on normal cultured human keratinocytes. HLA-DR expression was not induced on keratinocytes by recombinant alpha or beta interferons in a similar dose range nor by Con A or PHA. HLA-DR (L243) expression, as determined by FACS analysis, was detected as early as 1-2 days after addition of r-IFN-gamma to the cultures and was maximal after 4-8 days. Keratinocytes were analyzed for expression of another class II antigen, HLA-DC (Leu-10). Little or no expression of Leu-10 (DC) was detectable on these cells although Fc receptors for the IgG1 isotype were increased. These data indicate a unique role for gamma interferon in the differential regulation of keratinocyte class II antigen biosynthesis and expression. Induction of HLA-DR on keratinocytes may be functionally important in expanding the number of antigen presenting cells in the skin for the induction of an immune response and/or targeting these keratinocytes for cytolysis.

    View details for Web of Science ID A1985AFB5000003

    View details for PubMedID 3921630

  • ROLE OF MACROPHAGE D-REGION ANTIGENS AND LYMPHOCYTE-T DIFFERENTIATION ANTIGENS IN INDUCTION OF GAMMA INTERFERON JOURNAL OF INTERFERON RESEARCH Cunningham, A. L., BASHAM, T. Y., Para, M. F., Merigan, T. C. 1985; 5 (3): 477-491

    Abstract

    Macrophage-T-lymphocyte cultures from patients with recent recurrent herpes labialis were stimulated to produce gamma interferon by either herpes simplex antigen or mitogens (PHA and Con A). The ability of monoclonal antibodies to HLA-DR and DC/DS, HSV glycoprotein antigens and T-lymphocyte surface antigens to inhibit interferon production and lymphocyte proliferation were studied. Anti-D region antibodies inhibited HSV antigen-induced but not mitogen-induced interferon and proliferation. The extent of inhibition varied mainly according to the determinants recognized by the antibodies and, to a lesser degree, between patients. Inhibition probably resulted from inhibition of antigen presentation, through antibody binding to macrophage D-region antigens. Interferon production was a more sensitive index of inhibition than lymphocyte proliferation. With one antibody (L227) a marked difference in inhibition in the two assays was noted, suggesting that lymphocytes producing gamma interferon may differ from the majority of the proliferating cells in their recognition of D-region determinants. Antibodies to the HSV glycoprotein antigens (gA/B, gC, gD, gE) did not produce consistent significant inhibition of interferon production and had no effect on proliferation. Anti-Leu 4 and -Leu 5 inhibited HSV antigen and mitogen induction of gamma interferon (and proliferation). Anti-Leu 2 and anti-Leu 3, mildly inhibitory alone, produced synergistic inhibition together. Hence, in human systems, the interaction between macrophages and T lymphocytes in producing gamma interferon appears to differ according to mode of induction. Macrophage D-region antigens are required for antigen induction probably via presentation whereas other factor(s), probably monokine secretion, are necessary for mitogen induction. Antibodies acting on the T-lymphocyte surface appear to affect a final common pathway of interferon induction, similar to their effects on proliferation and secretion of other lymphokines.

    View details for Web of Science ID A1985ARK4500015

    View details for PubMedID 2997338

  • KERATINOCYTE CLASS-II HISTOCOMPATIBILITY ANTIGEN EXPRESSION BRITISH JOURNAL OF DERMATOLOGY Nickoloff, B. J., BASHAM, T. Y., Merigan, T. C., Morhenn, V. B. 1985; 112 (3): 373-374

    View details for Web of Science ID A1985ADV5400018

    View details for PubMedID 3856455

  • HUMAN INTERFERON ALPHA IN MALIGNANT-LYMPHOMA AND HODGKINS-DISEASE - RESULTS OF THE AMERICAN CANCER SOCIETY TRIAL CANCER Horning, S. J., Merigan, T. C., Krown, S. E., GUTTERMAN, J. U., Louie, A., Gallagher, J., MCCRAVEY, J., Abramson, J., Cabanillas, F., Oettgen, H., Rosenberg, S. A. 1985; 56 (6): 1305-1310

    Abstract

    Forty-nine patients with non-Hodgkin's lymphoma or Hodgkin's disease were entered into a multi-institutional phase II trial to evaluate the antitumor activity of human interferon alpha, prepared from buffy coats. Interferon alpha was administered intramuscularly in doses of 1 X 10(6) u, 3 X 10(6) u or 9 X 10(6) u daily for 30 days. Objective partial responses were seen in 3 of 18 patients with nodular lymphoma, all at the 9 X 10(6) u dose. Interferon alpha was not observed to be of therapeutic benefit in the other subtypes of non-Hodgkin's lymphoma or Hodgkin's disease. The major toxicities consisted of fatigue, fever, myalgias and weight loss. Serum interferon levels obtained 3 to 4 hours after injection varied widely, even among patients treated at the same dose level. Despite the relatively low doses of interferon used and the brief period of administration, this study extends the earlier observations of the antitumor effect of interferon in nodular lymphoma. These results are discussed in relation to the cumulative experience in human lymphoma using alpha interferons induced in human leukocytes and those produced in bacteria by recombinant DNA techniques.

    View details for Web of Science ID A1985APT3300013

    View details for PubMedID 4027869

  • TREATMENT OF NASOPHARYNGEAL CARCINOMA WITH HUMAN-LEUKOCYTE INTERFERON JOURNAL OF CLINICAL ONCOLOGY Connors, J. M., Andiman, W. A., Howarth, C. B., Liu, E., Merigan, T. C., Savage, M. E., Jacobs, C. 1985; 3 (6): 813-817

    Abstract

    Nasopharyngeal carcinoma (NPC) is a human neoplasm closely associated with Epstein-Barr virus (EBV). Human leukocyte interferon (IFN) has known antiviral and antineoplastic properties. After initial IFN treatment in one NPC patient demonstrated acceptably low toxicity, 12 additional patients were treated on a protocol with IFN, 10 X 10(6) units intramuscularly (IM) daily for 30 days. IFN did not affect serum anti-EBV antibody titers (IgA and IgG antiviral capsid and early antigens). Of six patients tested, none was found to excrete EBV in saliva before, during, or after IFN. Four patients had measurable tumor regression (two partial responses and two minor responses), three had stable disease, and five patients plus the initial preprotocol patient had progressive disease. Toxicity included fever, fatigue, and myalgias in all patients, thrombocytopenia in two patients, and neutropenia in three patients. Three patients were withdrawn from the study, one each for severe fatigue, neutropenia, and hypotension. This study demonstrates that IFN has sufficient activity in advanced NPC to justify further investigation.

    View details for Web of Science ID A1985AKC5500012

    View details for PubMedID 2989445

  • INTERFERON-GAMMA PRODUCTION BY HERPES-SIMPLEX VIRUS ANTIGEN-SPECIFIC T-CELL CLONES FROM PATIENTS WITH RECURRENT HERPES LABIALIS JOURNAL OF GENERAL VIROLOGY Cunningham, A. L., Nelson, P. A., Fathman, C. G., Merigan, T. C. 1985; 66 (FEB): 249-258

    Abstract

    Nineteen herpes simplex virus (HSV) antigen-specific human T lymphocyte clones were established from three volunteers with recent recurrent herpes labialis. All produced interferon gamma (IFN-gamma) at titres of 200 to 700 units/ml when cultured in vitro with HSV antigen and irradiated peripheral blood mononuclear cells (PBMC) as filler cells. All 10 of those clones whose phenotype was determined were Leu 4+, Leu 2-, Leu 3+. Interleukin 2 alone failed to induce IFN-gamma in titres greater than 10 units/ml from these clones cultured at 10(4)/0.2 ml/well. However, the effect of different accessory or filler cells on IFN-gamma production by clones was quite marked. For example, high titres were produced when irradiated PBMC or plastic-adherent cells (predominantly monocytes) were added and low titres when macrophages and irradiated Epstein-Barr virus-transformed B (EBV-B) cells were added. When tested for HSV antigen-stimulated IFN production alone, the irradiated PBMC and adherent cells produced low titres, but no detectable interferon was produced by the others. However, with higher concentrations of EBV-B cells, low concentrations of IFN-alpha were occasionally produced. Irradiation strikingly reduced IFN-alpha-production by PBMC. The IFN-alpha and -gamma produced by accessory cells may contribute to total IFN production by priming the production by cloned cells, and acting in synergy with IFN-gamma produced by the cloned cells. Alternatively, the effect may be due to the presence of permissive concentrations of other lymphokines such as the interleukins. Interferon production by cloned T lymphocytes in the presence of non-producing macrophages was maximal within 24 h, much faster than with a similar polyclonal system, although attaining lower titres. EBV-B cells from only one of three patients supported antigen-specific lymphocyte activation. Almost all cells of the three cell lines expressed DR antigens, while DS/DC antigens were also expressed on nearly all cells of the antigen-presenting line and, at lower densities, on two-thirds of the cells of the other two lines.

    View details for Web of Science ID A1985ACN1300004

    View details for PubMedID 2981967

  • IMMUNOMODULATORY AND ANTIPROLIFERATIVE EFFECT OF RECOMBINANT ALPHA-INTERFERONS, BETA-INTERFERONS, AND GAMMA-INTERFERONS ON CULTURED HUMAN-MALIGNANT SQUAMOUS-CELL LINES, SCL-1 AND SW-1271 JOURNAL OF INVESTIGATIVE DERMATOLOGY Nickoloff, B. J., BASHAM, T. Y., Merigan, T. C., Morhenn, V. B. 1985; 84 (6): 487-490

    Abstract

    Two different human malignant squamous cell lines (SCL-1 and SW-1271) and normal human foreskin fibroblasts were treated with recombinant human alpha, beta, and gamma interferons. HLA-DR expression was induced in a concentration-dependent fashion only on the SCL-1 cells treated with recombinant human gamma interferon (r-IFN-gamma) (10(2)-10(3) U/ml). No HLA-DR expression was observed with alpha or beta interferon on either malignant squamous cell line, nor with gamma interferon on SW-1271 cells. All three interferons reduced the number of malignant cells growing in culture but had no effect on the fibroblasts. There was a concentration-dependent growth-inhibitory response of the malignant cells by the interferons (dose range 1-10(3) U/ml; 7.1 X 10(-12) M to 7.1 X 10(-9) M). The SCL-1 cells were 10(2) more sensitive (based on weight) to the antiproliferative effects of gamma interferon than alpha or beta interferon. A brief (30-min) exposure of the SCL-1 cells to r-IFN-gamma (10(2) and 10(3) U/ml) produced approximately the same inhibition of cell growth as continuous exposure over a 2-week period. The SW-1271 cells were equally sensitive to alpha, beta, and gamma interferons. However, the maximal inhibitory effect on SW-1271 cells was less than that observed for the SCL-1 cells. Combining beta and gamma interferon resulted in cytotoxicity with SCL-1 cells and additive cytostatic effect on the SW-1271 cells. These additional malignant cell lines with their different sensitivities to alpha, beta, and gamma interferons may prove useful in studying the mechanisms of action of various interferons.

    View details for Web of Science ID A1985AJN5300008

    View details for PubMedID 3923127

  • HUMAN CYTOMEGALO-VIRUS POLYPEPTIDES STIMULATE NEUTRALIZING ANTIBODY INVIVO VIROLOGY Rasmussen, L., MULLENAX, J., Nelson, M., Merigan, T. C. 1985; 145 (1): 186-190

    Abstract

    At least three human cytomegalovirus polypeptides are targets for virus neutralizing antibody; a single protein of 86,000 molecular weight (p86) and two coimmunoprecipitating proteins of 130,000 and 55,000 molecular weight (p130/55). These polypeptides have been isolated by immunoaffinity chromatography and tested for immunogenicity in guinea pigs. Neutralizing antibody was detected after immunization with both p86 and p130/55. Hyperimmune sera to p130/55, but not p86, were dependent upon guinea pig complement for virus neutralization.

    View details for Web of Science ID A1985ANA0300019

    View details for PubMedID 2409670

  • PHASE-I EVALUATION OF A SYNTHETIC MUTANT OF BETA-INTERFERON CANCER RESEARCH Hawkins, M., Horning, S., Konrad, M., Anderson, S., Sielaff, K., ROSNO, S., SCHIESEL, J., Davis, T., deMets, D., Merigan, T., Borden, E. 1985; 45 (11): 5914-5920

    Abstract

    A synthetic mutant of beta-interferon, produced by recombinant DNA technology, was prepared with serine substituted for the naturally occurring cysteine at amino acid 17. This molecule, after purification to homogeneity, was evaluated in 23 patients with cancer for tolerated doses, safety, and pharmacokinetics. Each patient was begun on twice weekly administration, one dose i.m., then an identical dose i.v. Doses, escalated weekly, were tolerated by 9 of 12 patients at 100 X 10(6) units i.m., 11 of 14 patients at 100 X 10(6) units i.v., and 8 of 10 patients receiving i.v. doses of 200 X 10(6) units. Fever (greater than or equal to 38.9 degrees C), the commonest cause for ceasing dose escalation, occurred in 11 of 13 patients who developed limiting i.v. toxicity and 6 of 11 who developed limiting i.m. toxicity. Patients who did not have progressive cancer after completion of dose escalation received five consecutive daily doses at their maximum tolerated single dose by each route, i.m. and i.v. These two 5-day treatments were given without difficulty. All patients treated with 300 X 10(6) units or less, i.m. (n = 13) or i.v. (n = 10), were able to receive five daily doses without limiting toxicity. Peak serum titers occurred immediately after i.v. administration and declined in an exponential manner thereafter. Despite absence of measurable titers in serum after i.m. injection, fever and significant (P less than 0.05) depression of WBC and platelet counts, serum calcium, and serum cholesterol occurred (prestudy to maximum tolerated dose). An immunoglobulin antibody to beta-interferon, detected by enzyme-linked immunoabsorbent assay, developed in 17 of 23 patients. Neutralizing activity (titer 10(2] was found in only 1 of 23 patients. No immune-mediated sequelae (symptomatic or renal) were identified. Further Phase I and II trials with this molecule will determine whether it will prove to have a better therapeutic index or different spectrum of therapeutic activity from alpha-interferon or gamma-interferon.

    View details for Web of Science ID A1985ATM3000054

    View details for PubMedID 4053062

  • TRANSFUSION-ACQUIRED CYTOMEGALO-VIRUS INFECTION IN CARDIAC-SURGERY PATIENTS JOURNAL OF MEDICAL VIROLOGY Preiksaitis, J. K., GRUMET, F. C., Smith, W. K., Merigan, T. C. 1985; 15 (3): 283-290

    Abstract

    The incidence of transfusion-acquired primary cytomegalovirus (CMV) infection was studied in 483 cardiac surgery patients. Ninety-six patients (20%) were found to lack antibody to CMV [CMV Ab(-)] as measured by radioimmunoassay. Sixty-eight CMV Ab(-) were followed by viral culture and/or serology from eight weeks to one year after transfusion. Transfusion requirements in CMV Ab(-) patients were as follows: whole blood/packed red blood cells, mean 4.7 +/- 2.6 units; platelets (20 patients), 6.9 +/- 3.8 units; fresh frozen plasma (25 patients), mean 3.3 +/- 1.6 units. Forty-nine percent of 235 donor units tested had antibody to CMV. One donor unit (0.4%) had CMV-specific IgM. This was not associated with CMV infection in the recipient. One patient (1.5%) demonstrated evidence of seroconversion to CMV during the follow-up period. This is significantly less than reported in previously published studies (P less than .01). Serological methods used, the age of the transfused blood, the immune status of the transfusion recipient, and the administration of passive antibody in fresh frozen plasma are factors that may be responsible for the low incidence observed.

    View details for Web of Science ID A1985ACT8400008

    View details for PubMedID 2984327

  • VIRAL POLYPEPTIDES DETECTED BY A COMPLEMENT-DEPENDENT NEUTRALIZING MURINE MONOCLONAL-ANTIBODY TO HUMAN CYTOMEGALO-VIRUS JOURNAL OF VIROLOGY Rasmussen, L., MULLENAX, J., Nelson, R., Merigan, T. C. 1985; 55 (2): 274-280

    Abstract

    Murine monoclonal antibodies were produced which coimmunoprecipitated, under reducing conditions, 130,000- and 55,000-dalton (Da) polypeptides from cells infected with human cytomegalovirus (CMV) strain AD169. A 92,000-Da species, possibly a biosynthetic intermediate, was also detectable. One of the monoclonal antibodies, 15D8, neutralized CMV AD169 only in the presence of guinea pig complement. A second monoclonal antibody, 14E10, coimmunoprecipitated the 130,000- and 55,000-Da polypeptides but did not neutralize viral infectivity. By sequential immunoprecipitation, both monoclonal antibodies have been shown to recognize the same polypeptides. Monoclonal antibody 15D8 detected the 130,000- and 55,000-Da polypeptides in five of six clinical strains and three laboratory strains tested. The 14E10 monoclonal antibody detected the 130,000-Da protein in four of six CMV clinical isolates and in strain AD169 but did not immunoprecipitate any polypeptides from extracts of cells infected with either Towne or Davis laboratory strains. In kinetic studies, the synthesis of the 130,000-Da polypeptide preceded the appearance of the 55,000-Da polypeptide. In infected cells radiolabeled with a pulse of L-[35S]methionine, the isotope was initially detected in the 130,000-Da polypeptide but could be chased into the 55,000-Da polypeptide. These polypeptides exist in the intracellular and extracellular virus as disulfide-linked multimers. Extracellular virus contained a high-molecular-weight (greater than 200,000 Da) multimer composed entirely of 55,000-Da polypeptides. In extracts from infected cells an additional high-molecular-weight multimer was detected consisting of disulfide-linked 130,000-Da polypeptides.

    View details for Web of Science ID A1985ANU7400003

    View details for PubMedID 2410626

  • CYTOMEGALO-VIRUS INFECTION AND ABNORMAL LYMPHOCYTE-T SUBSET RATIOS IN HOMOSEXUAL MEN ANNALS OF INTERNAL MEDICINE Drew, W. L., Mills, J., Levy, J., Dylewski, J., CASAVANT, C., Ammann, A. J., Brodie, H., Merigan, T. 1985; 103 (1): 61-63

    Abstract

    T-helper:T-suppressor cell ratios of 1 or less were found in 2 of 42 homosexual men without antibodies to cytomegalovirus but in 33 of 67 homosexual men with antibodies (p less than 0.001). Of 34 men without antibody who were followed prospectively, 12 became seropositive for cytomegalovirus and all 12 developed helper: suppressor ratios of less than 1.0. These ratios remained at 1 or less for an average of 9.6 months but persisted for 15 months or more in 3 men. None of the men in the prospective study developed antibodies to the acquired-immunodeficiency-syndrome-associated retrovirus. These results indicate that in the homosexual men studied, abnormally low T-lymphocyte helper: suppressor ratios occurred almost exclusively in those who were infected with cytomegalovirus, and in those prospectively followed low ratios did not reflect contact with the syndrome-associated retrovirus. Abnormal ratios were rarely seen in men who had never been exposed to cytomegalovirus. Thus, cytomegalovirus infection may be an important cofactor in the immunologic disorders leading to the acquired immunodeficiency syndrome.

    View details for Web of Science ID A1985ALY3700013

    View details for PubMedID 2988392

  • EVOLUTION OF RECURRENT HERPES-SIMPLEX LESIONS - AN IMMUNOHISTOLOGIC STUDY JOURNAL OF CLINICAL INVESTIGATION Cunningham, A. L., Turner, R. R., Miller, A. C., Para, M. F., Merigan, T. C. 1985; 75 (1): 226-233

    Abstract

    We performed immunoperoxidase stains on skin biopsies taken from nine patients with recurrent peripheral herpes simplex lesions at 12 h to 6 d after onset of signs of symptoms to phenotype the inflammatory infiltrate, to detect cells producing interferons alpha and gamma, and to locate herpes simplex virus antigen-containing cells. Viral glycoprotein antigen was located in the nuclei and cytoplasm of necrotic epidermal cells, often within vesicles, in biopsies taken between the first and third day. Histologically, biopsies of all stages showed intradermal focal perivascular and diffuse mononuclear inflammatory infiltrates. The cells constituting the infiltrates were predominantly T lymphocytes with lesser numbers of histiocytes; Leu 7+ (most natural killer/killer) cells and B cells were rare in the biopsy specimens. Leu 3a+ ("helper") T lymphocytes predominated in both subepidermal and perivascular regions of early lesions (12-24 h). Tissue helper/suppressor ratios ranged from 6.3 to 3.4 compared with 1.9-1.0 in blood. In later lesions (after 2 d), monocytes/macrophages were more prominent in tissue sections and the helper/suppressor ratios (2.3-2.5) more nearly approximated those of blood (1.6-2.7). The negative correlation of tissue ratios with time was significant (P less than or equal to 0.02). A large proportion of the infiltrated T lymphocytes expressed DR antigens. There was also diffuse strong DR expression on epidermal cells in five cases (all of two or more days). In six biopsies, scattered macrophages and small cells, presumably lymphocytes, demonstrated cytoplasmic or membrane staining for a substance which copurifies with interferon gamma. We identified such stained cells within vessels, suggesting that these cells circulate. Gamma interferon might have an important role within the herpetic lesions, possibly inducing macrophage activation and cytotoxic T lymphocytes and increasing DR expression on monocyte and epidermal cells.

    View details for Web of Science ID A1985AAG6500032

    View details for PubMedID 3880773

  • INTRAVAGINAL APPLICATION OF LEUKOCYTE INTERFERON GEL IN THE TREATMENT OF CERVICAL INTRAEPITHELIAL NEOPLASIA (CIN) ARCHIVES OF GYNECOLOGY CHOO, Y. C., Hsu, C., Seto, W. H., MILLER, D. G., Merigan, T. C., NG, M. H., Ma, H. K. 1985; 237 (1): 51-54

    Abstract

    Leukocyte interferon gel (1 X 10(6) units) was applied twice daily by a vaginal applicator to areas of cervical intraepithelial neoplasia (CIN) in 7 patients. A partial response was obtained in 3 patients and complete response in 2 patients. This suggests that leukocyte interferon gel can be used to treat CIN.

    View details for Web of Science ID A1985ANV3800008

    View details for PubMedID 4051584

  • PRELIMINARY OBSERVATION OF HEPATITIS B-ASSOCIATED MEMBRANOUS GLOMERULONEPHRITIS TREATED WITH LEUKOCYTE INTERFERON HEPATOLOGY Garcia, G., Scullard, G., Smith, C., Weissberg, J., Alexander, S., Robinson, W. S., Gregory, P., Merigan, T. C. 1985; 5 (2): 317-320

    View details for Web of Science ID A1985AFD8700027

    View details for PubMedID 3979964

  • IMMUNOLOGICAL COMPLICATIONS IN MULTIPLE-SCLEROSIS PATIENTS RECEIVING INTERFERON ANNALS OF NEUROLOGY Rice, G. P., WOELFEL, E. L., Talbot, P. J., Braheny, S. L., Sipe, J. C., Knobler, R. L., Merigan, T. C., Oldstone, M. B. 1985; 18 (4): 439-442

    Abstract

    In a prospective, placebo-controlled study designed to test the efficacy of human alpha interferon (IFN) in the treatment of multiple sclerosis, we monitored several immunological functions. Interferon was shown to have many effects on the immune system, including activation of natural killer cells in vivo and elevation of serum immunoglobulin and cerebrospinal fluid IgG ratios. Furthermore, all patients who received IFN developed antibody titers to a protein contaminant (molecular weight, 27 kilodaltons) in the IFN preparation. This antibody was associated with an elevation in serum concentrations of C1q- and Raji-binding immune complexes in 6 of 12 patients. Some of these 12 patients developed symptoms suggestive of immune complex disease. IFN had pronounced effects on the immune system of these patients.

    View details for Web of Science ID A1985AUJ5300004

    View details for PubMedID 2416266

  • LEU-3+ T-CELLS PRODUCE GAMMA-INTERFERON IN PATIENTS WITH RECURRENT HERPES LABIALIS JOURNAL OF IMMUNOLOGY Cunningham, A. L., Merigan, T. C. 1984; 132 (1): 197-202

    Abstract

    Interferon-gamma (IFN-gamma) was spontaneously secreted by peripheral blood mononuclear cells cultured from patients soon after recurrent herpes labialis (RHL) or was induced from macrophage-T lymphocyte cultures in vitro with HSV antigen. Circulating Leu-3+/Leu-2- cells produced the spontaneous IFN almost exclusively. In the HSV antigen-stimulated culture system the same subset was the predominant producer of IFN-gamma. The IFN-gamma producing leu-3+ lymphocytes were plastic nonaderent but nylon wool adherent, and may be analagous to the murine Th 2 helper cell. In contrast to one lymphocyte subset being the major IFN-gamma producer in this viral disease, mitogen stimulation induced IFN-gamma from all (Leu-2+/2- and Leu-3+/3-) subsets, with panning as the separation technique. As mitogens circumvent the normal processing and presentation of antigen, the RHL system described above may provide a more accurate picture of the relative contributions of helper (Leu-3+) and cytotoxic/suppressor (Leu-2+) T cells to IFN-gamma production in herpes viral disease.

    View details for Web of Science ID A1984RV65800035

    View details for PubMedID 6418797

  • WHAT ARE WE GOING TO DO ABOUT AIDS AND HTLV-III LAV INFECTION NEW ENGLAND JOURNAL OF MEDICINE Merigan, T. C. 1984; 311 (20): 1311-1313

    View details for Web of Science ID A1984TR95700009

    View details for PubMedID 6092955

  • SURVIVAL IN CHRONIC HEPATITIS-B - AN ANALYSIS OF 379 PATIENTS ANNALS OF INTERNAL MEDICINE WEISSBERG, J. I., ANDRES, L. L., Smith, C. I., Weick, S., Nichols, J. E., Garcia, G., Robinson, W. S., Merigan, T. C., Gregory, P. B. 1984; 101 (5): 613-616

    Abstract

    Survival data from 379 patients with chronic hepatitis B were analyzed to determine life expectancy for the patient from the time of first contact. One hundred twenty-one patients had chronic persistent hepatitis, 128 had chronic active hepatitis, and 130 had chronic active hepatitis with cirrhosis. The frequency of symptoms (p less than 0.001), stigmata of chronic liver disease (p less than 0.001), and liver function test abnormalities (p less than 0.001) increased as the histologic features worsened, whereas the percentage of patients with circulating hepatitis B DNA polymerase declined (p less than 0.001). Women were uncommon in our series and had less severe disease than men (p less than 0.02). Fifty-one patients had died by the time of this analysis. The estimated 5-year survival rates were 97% for patients with chronic persistent hepatitis, 86% for those with chronic active hepatitis, and 55% for those with chronic active hepatitis with cirrhosis. The usual cause of death was liver failure and its sequelae. A multivariate analysis found age of 40 years or more, total bilirubin level of 1.5 mg/dL or more, ascites, and spider nevi to be factors that identified patients at a higher risk of death. The prognosis for patients with chronic hepatitis B is similar to that for patients with chronic hepatitis of other causes.

    View details for Web of Science ID A1984TR73200006

    View details for PubMedID 6486592

  • HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHIC ANALYSIS OF HYPOXANTHINE ARABINOSIDE IN PLASMA JOURNAL OF CHROMATOGRAPHY Smith, G. A., Giacomini, K. M., Smith, C. T., Gregory, P. B., Robinson, W. S., Merigan, T. C., Blaschke, T. F. 1984; 307 (2): 410-415

    View details for Web of Science ID A1984SU47300019

    View details for PubMedID 6203924

  • EXFOLIATIVE CYTOLOGY IN THE EVALUATION OF INTERFERON TREATMENT OF CERVICAL INTRAEPITHELIAL NEOPLASIA ACTA CYTOLOGICA Hsu, C., CHOO, Y. C., Seto, W. H., Pang, S. W., TAN, C. Y., Merigan, T. C., NG, M. H. 1984; 28 (2): 111-117

    Abstract

    Local interferon injection in four patients with cervical intraepithelial neoplasia (CIN) regularly elicited progressive regression of the lesions. The response was observed with exfoliative cytology after each injection, guided by colposcopic examination. The cytologic changes showed a cytocidal effect mainly on the dyskaryotic cells, preceded by cellular degeneration not unlike that of nonspecific inflammation and accompanied by an increase in neutrophil infiltration. The cytologic response was closely correlated with partial or complete clinical regression based on the absence of viable or degenerated dyskaryotic cells in the cervical smears. Three patients showed complete clinical regression after treatment. One patient showed recurrent viable dyskaryotic cells when the dosage was reduced, and treatment was suspended temporarily although her lesion had regressed completely after five injections. Clinical recurrence was noted one week after viable dyskaryotic cells reappeared in her smears. These observations suggest that cytology may be a useful means of monitoring interferon treatment in CIN.

    View details for Web of Science ID A1984SJ48000004

    View details for PubMedID 6583967

  • DNA OF 21 CLINICAL CYTOMEGALOVIRUS STRAINS DETECTED BY HYBRIDIZATION TO CLONED DNA FRAGMENTS OF LABORATORY STRAIN AD-169 JOURNAL OF MEDICAL VIROLOGY Chou, S., Roark, L., Merigan, T. C. 1984; 14 (3): 263-268

    Abstract

    Nine distinct DNA probes prepared from cloned DNA fragments of the cytomegalovirus (CMV) strain AD-169, each representing a relatively small portion of the total genome, were able to detect all 21 epidemiologically distinct clinical isolates of CMV that had been passaged in tissue culture. All probes were of comparable sensitivity in the detection of CMV, and under the hybridization conditions used, no probe gave an unusually high background with uninfected host cells.

    View details for Web of Science ID A1984TM26200009

    View details for PubMedID 6094724

  • DECREASED INTERFERON SYNTHESIS AND RESPONSIVENESS TO INTERFERON BY LEUKOCYTES FROM MULTIPLE-SCLEROSIS PATIENTS GIVEN NATURAL ALPHA-INTERFERON JOURNAL OF INTERFERON RESEARCH KAMINLEWIS, R. M., Panitch, H. S., Merigan, T. C., Johnson, K. P. 1984; 4 (3): 423-432

    Abstract

    Despite the use of interferon (IFN) in numerous clinical trials, relatively little is known about how IFN therapy influences leukocyte function. To evaluate some of its effects, leukocytes from multiple sclerosis (MS) patients given daily treatments of natural alpha IFN (IFN-alpha) were evaluated for IFN synthesis and two responses to IFN in vitro: enhancement (priming) of IFN synthesis and suppression of Concanavalin A (Con A)-induced T-cell mitogenesis. The IFN therapy had no effect on the sensitivity of Con A-stimulated leukocytes to the antiproliferative action of IFN-alpha. However, using Newcastle disease virus (NDV), measles virus, or poly I:C to stimulate IFN synthesis, cells from IFN-treated patients produced less IFN in response to all inducers, with titers ranging between 11% and 44% of pretherapy values. Also, unlike cells from these same patients before therapy or from the placebo recipients, cells from the IFN recipients were not primed by either IFN-alpha or -beta even though IFN-beta had not been used for therapy. The loss of these priming reactivities suggests that resistance to IFN had developed in IFN-treated patients.

    View details for Web of Science ID A1984TJ75900013

    View details for PubMedID 6333472

  • RECOMBINANT GAMMA-INTERFERON INDUCES HLA-DR EXPRESSION ON CULTURED HUMAN KERATINOCYTES JOURNAL OF INVESTIGATIVE DERMATOLOGY BASHAM, T. Y., Nickoloff, B. J., Merigan, T. C., Morhenn, V. B. 1984; 83 (2): 88-90

    Abstract

    In normal human epidermis, expression of HLA-DR antigen is restricted to Langerhans cells (LC) and acrosyringial epithelium. However, in diseases such as lichen planus and graft-vs.-host, HLA-DR antigen appears to be expressed by keratinocytes, although the exact source of the HLA-DR is unclear. Two possibilities are that (1) the HLA-DR is shed by neighboring immunocompetent cells, or (2) that the keratinocytes are synthesizing the antigen themselves. Recently, gamma interferon has been shown to induce HLA-DR biosynthesis and expression on human malignant melanoma cells lines and on normal vascular endothelium. We report here that pure recombinant human gamma interferon (100 units/ml) induces HLA-DR expression on 60-70% of cultured human adult keratinocytes depleted of LC within 2-4 days of culture as determined by fluorescence-activated cell sorter (FACS) analysis using monoclonal antibodies. No residual LC or lymphocytes could be detected in these cultures. This is the first demonstration of HLA-DR expression by cultured human keratinocytes. This expression may be of functional significance in antigen presentation and cell-mediated cytotoxicity involving the epidermis.

    View details for Web of Science ID A1984TD54000003

    View details for PubMedID 6206165

  • HUMAN-LEUKOCYTE INTERFERON ADMINISTRATION TO PATIENTS WITH SYMPTOMATIC AND SUSPECTED RABIES ANNALS OF NEUROLOGY Merigan, T. C., Baer, G. M., WINKLER, W. G., BERNARD, K. W., GIBERT, C. G., CHANY, C., Veronesi, R. 1984; 16 (1): 82-87

    Abstract

    Body fluids and brain tissue from rabid human patients have demonstrated only low titers of interferon. Therefore, pharmacokinetic studies of systemically administered and locally injected leukocyte interferon were performed in 2 North American patients with suspected rabies who showed no clinically important side effects of this therapy. Similar therapy was given to 5 patients with symptomatic rabies in Europe and America. Although no prolongation of the clinical course was seen in 3 patients given high-dose intraventricular and systemic therapy, treatment was not initiated until between 8 and 14 days after symptoms were seen. The intraventricular dosage regimen produced cerebrospinal fluid levels that appeared to fall progressively over the 24 hours after injection and demonstrated good but somewhat delayed distribution into the lumbar sac. Titers produced by this therapy were 30- to 10,000-fold higher than those normally observed in this infection, however. In the patients treated at the highest dosage, a diminished and delayed antirabies neutralizing antibody titer was observed, probably a result of the administration of the exogenous interferon.

    View details for Web of Science ID A1984TA19100014

    View details for PubMedID 6205625

  • COLLABORATIVE PHASE-I-II STUDY OF RECOMBINANT DNA-PRODUCED LEUKOCYTE INTERFERON (CLONE-A) IN METASTATIC BREAST-CANCER, MALIGNANT-LYMPHOMA, AND MULTIPLE-MYELOMA AMERICAN JOURNAL OF MEDICINE Quesada, J. R., Hawkins, M., Horning, S., Alexanian, R., Borden, E., Merigan, T., Adams, F., GUTTERMAN, J. U. 1984; 77 (3): 427-432

    Abstract

    Fifty-two patients with advanced cancer received sequentially escalating doses of 3 to 50 million units of recombinant DNA-produced alpha interferon by daily intramuscular injection. There were 23 patients with metastatic breast cancer, 17 patients with nodular poorly differentiated lymphocytic lymphoma, and 12 patients with multiple myeloma. Complete and partial remissions were obtained in 35 percent of patients with nodular poorly differentiated lymphoma, whereas rare activity was found in breast cancer and multiple myeloma. Dose-limiting toxicity occurred in patients receiving 36 million units or more and consisted of fatigue/asthenia, weight loss, and elevation of transaminase levels, requiring frequent interruption, reduction in dose, or cessation of treatment. Hematologic toxicity was rarely a limiting factor, but myelosuppression was severe in some patients with multiple myeloma. All toxicities were reversible on discontinuation of treatment. Antibodies to recombinant leukocyte A interferon were seen infrequently but may adversely affect therapy.

    View details for Web of Science ID A1984TH82000010

    View details for PubMedID 6548079

  • ANTIPROLIFERATIVE EFFECTS OF RECOMBINANT ALPHA-INTERFERONS AND GAMMA-INTERFERONS ON CULTURED HUMAN KERATINOCYTES LABORATORY INVESTIGATION Nickoloff, B. J., BASHAM, T. Y., Merigan, T. C., Morhenn, V. B. 1984; 51 (6): 697-701

    Abstract

    To extend our initial observation that recombinant gamma-interferon induced expression of class II major histocompatibility (HLA-DR) antigen on normal cultured human keratinocytes, we studied the antiproliferative effects of recombinant alpha- and gamma-interferons. Both interferons reduced the number of attached cells (dose range 10-10(3) units/ml; 7.1 X 10(-11) to 7.1 X 10(-9) M) and gamma-interferon was 100 times more potent than alpha. This effect did not require the presence of Langerhans cells. gamma-Interferon reduced total cell production during the first week without increasing the percentage of cells shed. During the second week, gamma-interferon also increased the percentage of cell shedding. Although 10(2) units/ml of gamma-interferon was maximal for HLA-DR expression by cultured keratinocytes, there was increasing reduction of attached cells between 10(2) to 10(3) units/ml. The demonstration that recombinant gamma-interferon induces HLA-DR expression and also inhibits keratinocyte proliferation in vitro at nanomolar concentration expands the growing list of normal cells whose biologic function may be influenced by this lymphokine in vivo.

    View details for Web of Science ID A1984TW47700012

    View details for PubMedID 6209471

  • COMPARISON OF ANTIVIRAL ACTIVITIES OF CLONED AND NATIVE HUMAN INTERFERONS AGAINST HERPES-SIMPLEX VIRUS TYPE-1 AND TYPE-2 AND HUMAN CYTOMEGALOVIRUS ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Rasmussen, L. E., Chen, P. T., Merigan, T. C. 1984; 26 (4): 599-600

    Abstract

    Five recombinant alpha interferons and two recombinant beta interferons have been tested for their ability to inhibit yields of herpes simplex virus types 1 and 2 and human cytomegalovirus in human embryonic lung cells. All of the alpha species and both of the beta forms (cysteine and serine) were active against the herpesviruses tested in this study. Neither the recombinant alpha nor the recombinant beta interferons exceeded the activity of the native species against herpes simplex viruses types 1 and 2. However, the recombinant beta interferons inhibited cytomegalovirus more than either the native beta or the alpha interferon species with the exception of interferon alpha K (alpha 6).

    View details for Web of Science ID A1984TM59500036

    View details for PubMedID 6097170

  • INTERFERON ENHANCES ANTIBODY-DEPENDENT CELLULAR CYTO-TOXICITY WHEN SUBOPTIMAL CONCENTRATIONS OF ANTIBODY ARE USED CELLULAR IMMUNOLOGY BASHAM, T. Y., Smith, W. K., Merigan, T. C. 1984; 88 (2): 393-400

    Abstract

    Polymorphonuclear leukocytes (PMN) and killer (K) cells isolated from buffy coats from normal volunteers were tested for antibody-dependent cellular cytotoxicity (ADCC) against chicken erythrocytes (CRBC) with and without the addition of interferon (IFN). Maximum enhancing activity was found when the anti-CRBC antibodies in the ADCC reaction were at suboptimal concentrations. All three species of pure recombinant Escherichia coli-derived interferon were compared for their ability to enhance ADCC in both effector systems. Recombinant IFN-gamma was found to be effective at lower doses than recombinant IFN-alpha A or recombinant IFN-beta, although maximum activity for all three species was similar in the PMN system. IFN-gamma also enhanced K-cell ADCC but to a lesser extent than in the PMN system. There appeared to be individual variation in response of the K-cell ADCC system to IFN-alpha A and IFN-beta at the doses tested.

    View details for Web of Science ID A1984TP48400015

    View details for PubMedID 6435886

  • LARGE-SCALE SEROLOGICAL SCREENING FOR CYTOMEGALOVIRUS ANTIBODIES IN HOMOSEXUAL MALES BY ENZYME-LINKED IMMUNOSORBENT-ASSAY JOURNAL OF CLINICAL MICROBIOLOGY Dylewski, J. S., Rasmussen, L., Mills, J., Merigan, T. C. 1984; 19 (2): 200-203

    Abstract

    We compared an enzyme-linked immunosorbent assay (ELISA) with complement fixation and radioimmunoassay in determining the presence of immunoglobulin antibodies to cytomegalovirus. Of an initial 93 serum samples tested, the correlation between ELISA and radioimmunoassay was 98.9% and that between ELISA and complement fixation was 96.1%. ELISA was used to screen 1,123 homosexual men in San Francisco. Of 479 men attending a homosexual health fair, 35 (7%) lacked cytomegalovirus antibodies by ELISA. Only 15 (2%) of 644 homosexual men attending a municipal sexually transmitted disease clinic were found to be seronegative. All but one of the seronegatives detected by ELISA were also seronegative by radioimmunoassay and complement fixation. We conclude that ELISA can be used to reliably perform large-scale screening for the presence of immunoglobulin G antibodies to cytomegalovirus.

    View details for Web of Science ID A1984SA45200026

    View details for PubMedID 6321545

  • CLINICAL-TRIAL OF NATURAL ALPHA INTERFERON IN MULTIPLE-SCLEROSIS ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Knobler, R. L., Panitch, H. S., Braheny, S. L., Sipe, J. C., Rice, G. P., HUDDLESTONE, J. R., Francis, G. S., Hooper, C. J., KAMINLEWIS, R. M., Johnson, K. P., Oldstone, M. B., Merigan, T. C. 1984; 436 (DEC): 382-388

    View details for Web of Science ID A1984AFT3700034

    View details for PubMedID 6398020

  • SYSTEMIC ALPHA-INTERFERON THERAPY OF MULTIPLE-SCLEROSIS NEUROLOGY Knobler, R. L., Panitch, H. S., Braheny, S. L., Sipe, J. C., Rice, G. P., HUDDLESTONE, J. R., Francis, G. S., Hooper, C. J., KAMINLEWIS, R. M., Johnson, K. P., Oldstone, M. B., Merigan, T. C. 1984; 34 (10): 1273-1279

    Abstract

    A randomized, double-blind, placebo-controlled crossover study tested the efficacy of natural alpha interferon in altering exacerbating-remitting MS. Twenty-four patients with frequent exacerbations were treated for 6-month periods, beginning with either 5 X 10(6) IU of interferon daily or placebo. A 6-month washout period followed each treatment. Exacerbation rates were reduced during interferon and placebo phases compared with pre-study rates; a greater reduction occurred on interferon, particularly following placebo, possibly reflecting a learning phenomenon. Fifteen patients with a strictly exacerbating-remitting course had fewer and milder exacerbations on interferon compared with those on placebo, whereas 9 patients with a progressive component continued to have active disease. These results suggest that interferon might reduce exacerbations in certain patients and indicate guidelines for future trials of interferon in MS.

    View details for Web of Science ID A1984TL81700001

    View details for PubMedID 6384817

  • ALPHA-INTERFERON ADMINISTRATION IN CYTOMEGALOVIRUS RETINITIS ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Chou, S., Dylewski, J. S., Gaynon, M. W., Egbert, P. R., Merigan, T. C. 1984; 25 (1): 25-28

    Abstract

    Four patients, including three with the acquired immunodeficiency syndrome (AIDS), were treated with high-dose, buffy coat-derived alpha-interferon for progressive cytomegalovirus retinitis. Two of these patients had decreased viruria during therapy and the other two had increased viruria. There was evidence of progression of disease despite therapy in all patients, although the retinitis eventually became quiescent in the patient without AIDS. The severe immunosuppression encountered in AIDS patients complicates the management of cytomegalovirus and other opportunistic infections.

    View details for Web of Science ID A1984RY30400007

    View details for PubMedID 6322678

  • INHIBITION OF HUMAN CYTOMEGALOVIRUS REPLICATION BY 9-(1,3-DIHYDROXY-2-PROPOXYMETHYL)GUANINE ALONE AND IN COMBINATION WITH HUMAN INTERFERONS ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Rasmussen, L., Chen, P. T., MULLENAX, J. G., Merigan, T. C. 1984; 26 (4): 441-445

    Abstract

    The inhibitory action of 9-(1,3-dihydroxy-2-propoxymethyl)guanine on the replication of human cytomegalovirus was studied. Three laboratory strains (AD-169, Towne, and Davis) and three early passage (less than 10) clinical isolates were all inhibited in yield inhibition assays. In cultures infected with AD-169, virus yields could be inhibited if the drug was added as late as 3 days after the replication cycle had begun. The effects of the drug were fully reversible during the first 4 days of the viral replication cycle. Viral infectivity and viral DNA synthesis were reduced more than viral protein synthesis. Synergistic antiviral effects were observed with beta-cysteine, and to a lesser extent, with beta-serine recombinant interferons, but only over a narrow range of dose combinations.

    View details for Web of Science ID A1984TM59500003

    View details for PubMedID 6097163

  • REGULATION OF EXPRESSION OF CLASS-II MAJOR HISTOCOMPATIBILITY ANTIGENS ON HUMAN PERIPHERAL-BLOOD MONOCYTES AND LANGERHANS CELLS BY INTERFERON HUMAN IMMUNOLOGY BASHAM, T., Smith, W., Lanier, L., Morhenn, V., Merigan, T. 1984; 10 (2): 83-93

    Abstract

    Although normal peripheral blood monocytes from different individuals are primarily DR+ (L243), they vary in the mean expression of L243 and the percentage of cells with detectable Leu-10 (DC/DS) and L03 (D). All three species of human recombinant IFNs enhance Ia expression on normal peripheral blood monocytes; however, r-IFN-gamma is much more effective in enhancing the expression of these three class II antigens in vitro than r-IFN-beta or r-IFN-alpha A. In addition, r-IFN-gamma has a more profound effect on the expression of Leu-10 (DC/DS), an antigen critical for presentation in autologous MLR, than on L243 (DR). Adherent monocytes cultured for 5 days develop macrophage characteristics and become strongly positive for all three of these class II antigens without further manipulation. Isolated skin Langerhans cells which are thought to be antigen presenting cells in the epidermis are also strongly positive for all three of these Ia antigens and are unaffected by IFN treatment. Therefore, this early interferon effect on cell surface expression may be the result of enhancing the maturation of monocytes to mature antigen presenting cells.

    View details for Web of Science ID A1984SU02500002

    View details for PubMedID 6203882

  • MURINE MONOCLONAL-ANTIBODY TO A SINGLE PROTEIN NEUTRALIZES THE INFECTIVITY OF HUMAN CYTOMEGALOVIRUS PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES Rasmussen, L. E., Nelson, R. M., KELSALL, D. C., Merigan, T. C. 1984; 81 (3): 876-880

    Abstract

    Murine monoclonal antibodies to human cytomegalovirus (CMV) strain AD169 were selected that neutralized virus infectivity. One monoclonal antibody-producing hybridoma, 1G6, was used to produce ascites fluid from which immunoglobulin was isolated. This antibody efficiently neutralized CMV AD169, other laboratory strains (Towne, Davis), and clinical isolates of CMV in early tissue culture passage (less than 10) in the absence of complement. The antibody immunoprecipitated a single 86,000-dalton protein from both laboratory and clinical strains. This viral protein was demonstrated by indirect immunofluorescence to be localized in the cytoplasm of CMV-infected cells.

    View details for Web of Science ID A1984SF38800050

    View details for PubMedID 6199788

  • RECOMBINANT INTERFERON-GAMMA INCREASES HLA-DR SYNTHESIS AND EXPRESSION JOURNAL OF IMMUNOLOGY BASHAM, T. Y., Merigan, T. C. 1983; 130 (4): 1492-1494

    Abstract

    It has been shown that all three classes of interferons enhance the expression of the major histocompatibility class I antigens (HLA-A,B,C;H-2) on a wide variety of cell types (1-10). However, their effect on the expression of the class II antigens (HLA-DR, Ia), which play a major part in cellular interactions that initiate an immune response, is more controversial. The predominate findings have been that the interferons specifically increase the synthesis and expression of only the class I antigens (3, 4, 6, 8, 10, 11). We report here that recombinant interferon-gamma (IFN-gamma) increases the synthesis and expression of the HLA-DR (la-like) antigens as well as beta 2-microglobulin (beta 2-m), a low m.w. subunit of HLA, on human melanoma cells. No increase in HLA-DR was detected on these melanoma cells with leukocyte interferon (IFN-alpha) at doses 400 times higher than the maximum dose of IFN-gamma. These findings were extended to show that pure IFN-gamma also increases the expression of the HLA-DR antigens on normal peripheral blood monocytes, whereas recombinant IFN-alpha at a similar dose had little effect on the expression of this surface antigen. These findings suggest a specialized role for IFN-gamma in immune regulation in comparison with IFN-alpha.

    View details for Web of Science ID A1983QG84000002

    View details for PubMedID 6403609

  • HUMAN INTERFERON AS A THERAPEUTIC AGENT - CURRENT STATUS NEW ENGLAND JOURNAL OF MEDICINE Merigan, T. C. 1983; 308 (25): 1530-1531

    View details for Web of Science ID A1983QV27100010

    View details for PubMedID 6190083

  • NATURAL-KILLER CELL-ACTIVITY IN PATIENTS WITH MULTIPLE-SCLEROSIS GIVEN ALPHA-INTERFERON ANNALS OF NEUROLOGY Rice, G. P., Casali, P., Merigan, T. C., Oldstone, M. B. 1983; 14 (3): 333-338

    Abstract

    The purpose of this study was to examine the function and regulation of natural killer cells in vitro and in vivo in patients with multiple sclerosis. Of 12 patients who received 5 X 10(6) international units of human alpha interferon, 9 demonstrated an increase in natural killer cell activity within 48 hours as defined by the lysis of 51Cr-labeled K-562 cells. The activity was normal before treatment, unlike that of tumor-bearing patients, and reached baseline levels within one week despite continuous interferon administration over the next six months. The same patients given a placebo preparation failed to show this enhanced natural killer cell activity. We also studied K-562 killing in 36 other patients and age- and sex-matched control subjects and were unable to demonstrate any differences between the two groups or any correlation of natural killer cell function with disease activity. The in vitro augmentation of natural killer cell activity by purified measles virions, which is associated with the release of interferon, and by the isolated glycoproteins of measles virus, which activates natural killer cells without the extracellular release of interferon, was similar in both patients and control subjects. Further, the proportion of cells defined by the monoclonal antibody HNK-1, which defines both natural killer cells and a small subset of cytotoxic T lymphocytes, was normal. In patients with multiple sclerosis, the normality of natural killer cell function, as defined by these several interrelated assays, speaks against a defect in this nonspecific antiviral defense mechanism in the pathogenesis of the disease.

    View details for Web of Science ID A1983RF88500011

    View details for PubMedID 6638954

  • ABSENCE OF DETECTABLE IGM ANTIBODY DURING CYTOMEGALOVIRUS DISEASE IN PATIENTS WITH AIDS NEW ENGLAND JOURNAL OF MEDICINE Dylewski, J., Chou, S., Merigan, T. C. 1983; 309 (8): 493-493

    View details for Web of Science ID A1983RD53300014

    View details for PubMedID 6308449

  • INFECTIONS DUE TO HERPESVIRUSES IN CARDIAC TRANSPLANT RECIPIENTS - ROLE OF THE DONOR HEART AND IMMUNOSUPPRESSIVE THERAPY JOURNAL OF INFECTIOUS DISEASES Preiksaitis, J. K., ROSNO, S., Grumet, C., Merigan, T. C. 1983; 147 (6): 974-981

    Abstract

    The role of the donor heart and immunosuppressive therapy on infection due to herpesviruses in 74 cardiac transplant recipients (CTRs) was determined. When cellular blood products from donors seronegative for antibody to cytomegalovirus (anti-CMV) were used, all primary CMV infections were attributable to transmission from donor heart. None of eight CTRs negative for anti-CMV before transplant and who received an anti-CMV donor heart and anti-CMV blood products developed CMV infection compared to one (20%) of five who received unscreened blood. A change from high-dosage anti-thymocyte globulin, azothioprine, and prednisone (ATG regimen) to low-dosage anti-thymocyte globulin, cyclosporin A, and prednisone (CsA regimen) significantly decreased the severity and prevalence of lesions due to herpes simplex virus and the duration of CMV shedding in patients with recurrent CMV infection. CTRs with recurrent CMV infection treated with the ATG regimen had significantly more fever, required more parenteral antibiotics, and were more likely to be infected with opportunistic pathogens than were CsA-treated patients.

    View details for Web of Science ID A1983QW73900002

    View details for PubMedID 6304206

  • ACUTE DANE PARTICLE SUPPRESSION WITH RECOMBINANT LEUKOCYTE-A INTERFERON IN CHRONIC HEPATITIS-B VIRUS-INFECTION JOURNAL OF INFECTIOUS DISEASES Smith, C. I., Weissberg, J., Bernhardt, L., Gregory, P. B., Robinson, W. S., Merigan, T. C. 1983; 148 (5): 907-913

    Abstract

    The clinical, virologic, biochemical, and immunologic effects of a biosynthetic human leukocyte interferon, recombinant leukocyte A interferon (rIFN-A or HuIFN-alpha 2) are reported in nine patients with chronic hepatitis B virus infection and circulating Dane particle-associated polymerase activity. Eight-day courses of rIFN-A were given starting at a dose of 3 X 10(6) units per day and reaching 68 X 10(6) units per day in two patients. Major toxic side effects included fever, fatigue, gastrointestinal symptoms, myalgias, and headache. Most courses of rIFN-A were associated with a reduction in Dane particle-associated polymerase activity, but in no case was this change permanent. There were also changes in lymphocyte subpopulations at the higher dosage levels of rIFN-A. Because of the reproducible, statistically significant effect on viral replication, further study with this and other biosynthetic interferon species is warranted.

    View details for Web of Science ID A1983RR57200018

    View details for PubMedID 6631076

  • RAPID DETECTION AND QUANTITATION OF HUMAN CYTOMEGALOVIRUS IN URINE THROUGH DNA HYBRIDIZATION NEW ENGLAND JOURNAL OF MEDICINE Chou, S., Merigan, T. C. 1983; 308 (16): 921-925

    Abstract

    We detected cytomegalovirus DNA in clinical urine specimens after immobilization on nitrocellulose filters and hybridization with a radioactively labeled, cloned fragment of cytomegalovirus DNA. We accomplished the specific detection and quantitation of viral DNA within 24 hours with 39 urine specimens from nine patients with cytomegalovirus viruria, mostly at a tissue-culture infective titer of 10(3) per milliliter or higher. None of 57 urine specimens from 21 patients that were culture-negative for cytomegalovirus gave false-positive results. Analysis of specimens from patients with cytomegalovirus viruria showed a correlation of the infective titer with the intensity of DNA hybridization (r = 0.77). Hybridization of sequential urine specimens from a patient undergoing treatment with interferon for cytomegalovirus retinitis revealed quantitative variations in hybridizable viral DNA over a period that correlated with clinical findings. This assay can be useful in the selection of patients for antiviral therapy and for the assessment of its efficacy.

    View details for Web of Science ID A1983QL58800003

    View details for PubMedID 6300675

  • GAMMA-INTERFERON PRODUCTION APPEARS TO PREDICT TIME OF RECURRENCE OF HERPES LABIALIS JOURNAL OF IMMUNOLOGY Cunningham, A. L., Merigan, T. C. 1983; 130 (5): 2397-2400

    Abstract

    Peripheral blood mononuclear cells separated from the blood of 29 volunteers within 3 wk of the onset of recurrent oral herpes labialis spontaneously secreted IFN-gamma (and small amounts of IFN-beta) into the culture medium in varying amounts (mean = 77 U/ml, SE = 17). However, interferon could not be detected in the serum of 10 of these patients tested. In the group as a whole, peak levels of interferon were secreted in vitro at 6 to 20 days after the onset of herpes labialis. Serial studies in eight patients showed peak production in the second or third week, with subsequent decrease to undetectable levels at 6 wk. A strong correlation between peak supernatant interferon level and the time to the next recurrence of herpes labialis in each patient was noted (r = 0.82, p less than 0.0001). Herpes simplex antigen-stimulated mononuclear cell cultures from each patient produced a mixture of IFN-alpha and IFN-gamma. A less marked but still significant correlation was noted between the peak mixed interferon level and the inter-recurrence interval (r = 0.52, p less than 0.005). These results suggest that a recurrent herpes labialis acts as an in vivo stimulus to the induction of IFN-gamma-producing cells that circulate in peripheral blood. The IFN-gamma produced is either a direct determinant of frequency of recurrence of herpes or a quantitative marker for other cellular immune events determining frequency.

    View details for Web of Science ID A1983QL86600076

    View details for PubMedID 6403619

  • PHASE-I STUDY OF HUMAN-LEUKOCYTE INTERFERON IN PATIENTS WITH ADVANCED CANCER JOURNAL OF BIOLOGICAL RESPONSE MODIFIERS Horning, S. J., Levine, J. F., Meyer, M., Merigan, T. C., Rosenberg, S. A. 1983; 2 (1): 47-56

    Abstract

    Seventeen patients with disseminated cancer were treated with a human leukocyte interferon preparation in doses ranging from 3 X 10(6) to 50 X 10(6) IU daily for 30 days. Doses above 18 X 10(6) IU were considered intolerable in this schedule of administration due to severe fatigue and weight loss. Serum concentrations of interferon were lower than those achieved with either partially pure native or recombinant leukocyte interferon. Three of 17 patients in this study showed minimal evidence of tumor regression. Two patients treated at doses of 18 X 10(6), 36 X 10(6), and 50 X 10(6) IU also received a 5 X 10(6)-IU dose of a second human leukocyte interferon preparation. The latter resulted in less toxicity but similar serum levels. These results suggest that human leukocyte interferons prepared in the same manner may differ significantly in their in vivo biologic properties.

    View details for Web of Science ID A1983RF47400003

    View details for PubMedID 6196450

  • GROWTH-REGULATION OF MELANOMA-CELLS BY INTERFERON AND (2'-5')OLIGOADENYLATE SYNTHETASE MOLECULAR AND CELLULAR BIOLOGY Creasey, A. A., Eppstein, D. A., MARSH, Y. V., Khan, Z., Merigan, T. C. 1983; 3 (5): 780-786

    Abstract

    We report that endogenous, as well as exogenous, interferon (IFN) regulates the growth of human melanoma cells in culture. When antibodies directed against human fibroblast IFN were incorporated into the media of high-density cells stimulated to proliferate with serum, the cells entered the cell cycle earlier than did the controls. In investigating the biochemical basis for this finding, we have found that there is an inverse relationship between the (2'-5')oligoadenylate synthetase levels and the percentage of cells in S in untreated cultures. Upon IFN treatment, the relationship is obliterated and (2'-5')oligoadenylate synthetase levels increase throughout all phases of the cell cycle. This increase in enzyme levels correlates well with the decreased probability of the IFN-treated cells to cycle. These findings suggest a biological role for IFN as a negative growth factor for cells in culture.

    View details for Web of Science ID A1983QN67600004

    View details for PubMedID 6865941

  • INTERFERON PROPHYLAXIS AGAINST SIMIAN VARICELLA IN ERYTHROCEBUS-PATAS MONKEYS JOURNAL OF INFECTIOUS DISEASES Arvin, A. M., Martin, D. P., GARD, E. A., Merigan, T. C. 1983; 147 (1): 149-154

    Abstract

    Erythrocebus patas monkeys were given placebo or human leukocyte interferon (5 x 10(5) units/kg of body weight per day im) for five days during an epizootic of simian varicella. During the 14 days beginning with the first day of treatment, the attack rate for simian varicella was 14.3% (two of 14) among interferon recipients compared to 70% (nine of 13) among placebo recipients (P less than 0.025). Excluding animals with antibody to simian varicella when the study began, 18% (two) of 11 interferon recipients had symptoms of infection compared to 80% (nine) of 11 placebo recipients (P less than 0.025). The epizootic began in a room housing male animals. The incidence of infection in male placebo recipients was 100% (seven of seven) compared to 14% (one of seven) in male interferon recipients (P less than 0.01). The efficacy of interferon prophylaxis in the simian varicella model supports its continued evaluation for the management of human varicella in high-risk patients.

    View details for Web of Science ID A1983QA17200020

    View details for PubMedID 6296238

  • Infectious Diseases Society of America. Trials of interferon therapy for multiple sclerosis. journal of infectious diseases Abb, J., DEINHARDT, F., Zander, H., Tenser, R. B., Rapp, F., Goust, J. M., FUDENBERG, H. H., Vilcek, J., Ho, M., Merigan, T. C., Oldstone, M. B., Jackson, G. G. 1982; 146 (1): 109-115

    View details for PubMedID 6177805

  • Cytomegalovirus infection in heart transplant recipients: preliminary results of a controlled trial of intravenous gamma globulin. Journal of clinical immunology Preiksaitis, J. K., ROSNO, S., Rasmussen, L., Merigan, T. C. 1982; 2 (2): 36S-41S

    View details for PubMedID 6177709

  • Use of intravenous immune globulin in patients receiving bone marrow transplants. Journal of clinical immunology Winston, D. J., Ho, W. G., Rasmussen, L. E., Lin, C. H., Chu, H. L., Merigan, T. C., Gale, R. P. 1982; 2 (2): 42S-47S

    Abstract

    Patients undergoing bone marrow transplantation for acute leukemia or aplastic are a great risk for the development of interstitial pneumonia associated with the cytomegalovirus (CMV). Passive immunization with a CMV immune plasma has been found to be effective for the prevention of interstitial pneumonia after marrow transplantation. Because of the limited availability of high-titered CMV plasma, we studied the kinetics of CMV antibody in bone marrow transplant patients receiving immune globulin intravenous, 5%, in 10% maltose (IGIV). Several lots of IGIV had CMV radioimmunoassay (RIA) antibody titers (1:30,000) comparable to the CMV antibody titers in the CMV immune plasma. A single infusion of 20 cc/kg of IGIV produced a mean peak CMV RIA antibody titer of 1:9,500. This titer fell to 1:1,000 after seven days. These antibody titers were approximately two-to three-fold lower than the CMV RIA antibody titers achieved after a 10 cc/kg dose of the CMV immune plasma. Administration of IGIV at doses lower than 20 cc/kg produced correspondingly lesser increases in the CMV antibody titers of recipients. At all doses, IGIV was well tolerated and caused no significant biochemical abnormalities. Some patients experienced mild elevation of their serum glucose levels and asymptomatic glycosuria. We are presently evaluating the efficacy of IGIV (20 cc/kg given once every week) for the modification of CMV infection and prevention of interstitial pneumonia after bone marrow transplantation in a randomized, controlled study. The effects of IGIV on the incidence and outcome of bacterial, fungal, and other viral infections are also being analyzed.

    View details for PubMedID 6282926

  • PRELIMINARY STUDIES OF ACYCLOVIR IN CHRONIC HEPATITIS-B AMERICAN JOURNAL OF MEDICINE Smith, C. I., SCULLARD, G. H., Gregory, P. B., Robinson, W. S., Merigan, T. C. 1982; 73 (1A): 267-270

    Abstract

    Three patients with HBsAg-positive and DNA-polymerase-positive chronic hepatitis were treated with increasing dosages of intravenous acyclovir. A fall in DNA polymerase activity was seen with all courses of acyclovir but no dose-response relationship was evident. In only one patient did DNA polymerase fall to zero where it has remained for five months. Two out of 10 courses were associated with significant side effects with the highest dosages of acyclovir but these promptly resolved when the agent was stopped. Acyclovir's apparently partial and transient action suggests that it will not have a role in the treatment of chronic hepatitis B virus infection.

    View details for Web of Science ID A1982NZ89000052

    View details for PubMedID 7102705

  • CYTOMEGALOVIRUS IMMUNE PLASMA IN BONE-MARROW TRANSPLANT RECIPIENTS ANNALS OF INTERNAL MEDICINE Winston, D. J., Pollard, R. B., Ho, W. G., Gallagher, J. G., Rasmussen, L. E., HUANG, S. N., Lin, C. H., GOSSETT, T. G., Merigan, T. C., Gale, R. P. 1982; 97 (1): 11-18

    Abstract

    The effects of passive immunization on cytomegalovirus infection and interstitial pneumonia in marrow transplants were evaluated in a randomized, controlled trial. Twenty-four patients received cytomegalovirus immune plasma before and after transplantation, and 24 patients were controls. Although the incidence of cytomegalovirus infection was similar in the control and plasma groups, symptomatic infection (12 of 24 versus five of 24, p = 0.07) and interstitial pneumonia (11 of 24 versus five of 24, p = 0.12) occurred less frequently in the group receiving plasma. Cytomegalovirus infection occurred in 11 of 13 recipients of leukocyte transfusions and in 16 of 35 patients not given leukocyte transfusions (p = 0.02). Among patients not given leukocyte transfusions, the incidence of cytomegalovirus infection was similar in the control and plasma groups, but symptomatic infection (eight of 18 versus one of 17, p = 0.03) and interstitial pneumonia (nine of 18 versus one of 17, p = 0.01) were significantly less in the group receiving plasma. These results suggest that passive immunization modifies cytomegalovirus infection in humans and prevents interstitial pneumonia in marrow transplants especially when leukocyte transfusions are not used.

    View details for Web of Science ID A1982NX68400003

    View details for PubMedID 6283982

  • SYSTEMIC ANTI-VIRAL FOR THERAPY OF HERPESVIRUS DISEASES DEVELOPMENTS IN BIOLOGICAL STANDARDIZATION Merigan, T. C. 1982; 52: 527-533

    Abstract

    Several chemicals and interferons have been utilized in the prophylaxis and the treatment of a number of human herpesvirus infections. For example, adenine arabinoside as well as acyclovir and human leukocyte interferon appear active against acute varicella zoster and herpes simplex infections in controlled trials. Some of these agents have transient in vivo actions against CMV and EBV as well. Further open trial work with these 2 viruses appears necessary to improve dose regimens or to employ combination therapy or study new derivatives or agents before controlled trials are warranted. Recombinant DNA methodology is currently providing much greater yields of pure interferon for such uses. Recent successes in eradicating chronic hepatitis B virus infection suggest that it is even possible in the future that persistent herpesviruses in the CNS or lymphoreticular systems may be amenable to long-term therapy. As hyperimmune globulin appears to diminish the severity of CMV disease, it is also possible that human monoclonal antibodies may provide a useful approach for immunoprophylaxis as therapy.

    View details for Web of Science ID A1982QB89000051

    View details for PubMedID 6187616

  • ANTIVIRAL TREATMENT OF CHRONIC HEPATITIS-B VIRUS-INFECTION - PHARMACOKINETICS AND SIDE-EFFECTS OF INTERFERON AND ADENINE-ARABINOSIDE ALONE AND IN COMBINATION ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Sacks, S. L., SCULLARD, G. H., Pollard, R. B., Gregory, P. B., Robinson, W. S., Merigan, T. C. 1982; 21 (1): 93-100

    Abstract

    In an uncontrolled trial, 29 patients with chronic hepatitis B virus infection were treated with 93 courses of adenine arabinoside at doses ranging from 2.5 to 15 mg/kg per day. Most patients were treated concomitantly with human leukocyte interferon. Significant, but transient, neurotoxicity was seen with adenine arabinoside therapy in 44% of all courses. Manifestations of toxicity were mainly neurological and ranged from pain syndromes to tremors and, rarely, seizures. Suppression of numbers of lymphocytes was also noted. All effects were reversible with time. The extent of toxicity was dependent upon the dosage of adenine arabinoside. Treatment with interferon appeared to potentiate the occurrence of toxicity with adenine arabinoside. Arabinofuranosylhypoxanthine serum levels increased in a dose-dependent manner and tended to accumulate in interferon-treated hepatitis patients during a course of therapy. Elevated blood levels and drug accumulation were associated with toxicity in a significant fashion. Human leukocyte interferon was administered to 38 patients in 113 separate courses. Interferon side effects were rapidly reversible upon cessation of therapy. These included initial fever, myalgias, and hair loss as well as suppression of granulocytes, platelets, and lymphocytes in the blood.

    View details for Web of Science ID A1982MX19200016

    View details for PubMedID 6177285

  • CYTOMEGALOVIRUS-INFECTION IN HEART-TRANSPLANT RECIPIENTS - PRELIMINARY-RESULTS OF A CONTROLLED TRIAL OF INTRAVENOUS GAMMA-GLOBULIN JOURNAL OF CLINICAL IMMUNOLOGY Preiksaitis, J. K., ROSNO, S., Rasmussen, L., Merigan, T. C. 1982; 2 (2): S36-S41
  • INTERFERON - THE 1ST QUARTER CENTURY JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Merigan, T. C. 1982; 248 (19): 2513-2516

    View details for Web of Science ID A1982PP74600034

    View details for PubMedID 6182308

  • ALPHA INTERFERON ADMINISTRATION TO INFANTS WITH CONGENITAL-RUBELLA ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Arvin, A. M., Schmidt, N. J., CANTELL, K., Merigan, T. C. 1982; 21 (2): 259-261

    Abstract

    Three infants with congenital rubella syndrome were given human leukocyte (alpha) interferon at doses of 2 x 10(5) to 7 X 10(5) U/kg per day for 10 days. A transient decrease in pharyngeal virus excretion was observed with treatment. No significant side effects were associated with the administration of human leukocyte interferon to these infants.

    View details for Web of Science ID A1982NB67200012

    View details for PubMedID 6176183

  • HUMAN-LEUKOCYTE INTERFERON FOR THE TREATMENT OF VARICELLA IN CHILDREN WITH CANCER NEW ENGLAND JOURNAL OF MEDICINE Arvin, A. M., KUSHNER, J. H., Feldman, S., Baehner, R. L., Hammond, D., Merigan, T. C. 1982; 306 (13): 761-765

    Abstract

    Human leukocyte interferon was evaluated as a treatment for varicella in a randomized double-blind, placebo-controlled study carried out in two phases. A total of 44 children being treated for cancer were enrolled within 72 hours of the appearance of the exanthem. The mean number of days of new lesion formation was 3.8 +/- 1.89 (+/- S.D.) in the interferon recipients and 5.3 +/- 2.56 in the placebo recipients (P less than 0.05). Eighty-one per cent of the interferon recipients had had no new lesions for 24 hours by Day 7, as compared with 56 per cent of the placebo recipients (P less than 0.025). In the second, higher-dose phase of the study 92 per cent of the interferon recipients had had no new lesions for 24 hours by Day 6, as compared with 45 per cent of the placebo recipients (P less than 0.025). Three of 21 placebo recipients died of progressive varicella. Two of the 23 interferon recipients died two to three weeks after the onset of varicella; viral cultures were negative in one of these patients, and the second had recurrent viremia at the end of the treatment period. Among the survivors, treatment with interferon reduced the number of patients who had life-threatening dissemination (none of 21 vs. three of 18; P = 0.053). We conclude that interferon had an antiviral effect against varicella virus in immunocompromised patients.

    View details for Web of Science ID A1982NG94400001

    View details for PubMedID 6174864

  • SPECIFIC CELL-MEDIATED-IMMUNITY AND INFECTIONS WITH HERPES VIRUSES IN CARDIAC TRANSPLANT RECIPIENTS AMERICAN JOURNAL OF MEDICINE Pollard, R. B., Arvin, A. M., Gamberg, P., RAND, K. H., Gallagher, J. G., Merigan, T. C. 1982; 73 (5): 679-687

    Abstract

    Immune responses and infections with herpes viruses were studied prospectively in 36 cardiac transplant recipients. Specific lymphocyte transformation and interferon production in response to viral antigens, viral culture results, antibody levels, responses to phytohemagglutinin, and T-cell numbers were determined. Responses to phytohemagglutinin and T-cell numbers were depressed for six to 12 weeks. Cytomegalovirus infection occurred in 100 percent of seropositive patients and in 62 percent of seronegative patients. Primary infection was more frequently symptomatic. Heart implantation from a seropositive patient wwas significantly correlated with subsequent infection in seronegative patients. Depression of transformation in response to cytomegalovirus correlated with prolonged shedding. Herpes simplex infection occurred in 95 percent of seropositive patients but decreased after 12 weeks. Asymptomatic shedding was rare, and primary infection did not occur. Return of transformation in response to herpes simplex was associated with decreased infection. Herpes zoster occurred in 22 percent during the first year, and transformation responses to varicella-zoster returned thereafter. Depression of interferon production in response to viruses did not correlate with infection as well as did lymphocyte transformation.

    View details for Web of Science ID A1982PQ69700012

    View details for PubMedID 6291387

  • VIRUS-SPECIFIC IGG AND IGM ANTIBODIES IN NORMAL AND IMMUNOCOMPROMISED SUBJECTS INFECTED WITH CYTOMEGALOVIRUS JOURNAL OF INFECTIOUS DISEASES Rasmussen, L., Kelsall, D., Nelson, R., Carney, W., Hirsch, M., Winston, D., Preiksaitis, J., Merigan, T. C. 1982; 145 (2): 191-199

    Abstract

    Levels of IgG and IgM antibodies t human cytomegalovirus (CMV) were measured using a solid-phase radioimmunoassay. Individuals positive by complement-fixation test consistently had detectable IgG titers by radioimmunoassay, but no quantitative relationship was apparent. An elevated IgM titer was considered specific for CMV infection because sera from individuals with other herpesvirus infections did not cross-react. In patients with mononucleosis, elevated titers of IgM antibody to CMV correlated (P less than 0.001) with active infection and were highest during viremia. Titers of IgG antibody to CMV during and after symptomatic infection were similar to those of asymptomatic positive individuals. Increases in CMV-specific IGM were observed in both primary and reactivated infections in cardiac transplant recipients. In a small group of cardiac transplant recipients with recurrent symptomatic disease, IgM titers were low at the time of viruria and did not increase with CMV tissue involvement, a result which suggests that quantitative deficiencies in IgM may be related to the severity of CMV infections.

    View details for Web of Science ID A1982NB26800008

    View details for PubMedID 6274969

  • INTERFERON REDUX NATURE Friedman, R. M., Epstein, L. B., Merigan, T. C. 1982; 296 (5859): 704-705

    View details for Web of Science ID A1982NL32100021

    View details for PubMedID 6175908

  • ANTIVIRAL TREATMENT OF CHRONIC HEPATITIS-B VIRUS-INFECTION - INFECTIOUS VIRUS CANNOT BE DETECTED IN PATIENT SERUM AFTER PERMANENT RESPONSES TO TREATMENT HEPATOLOGY SCULLARD, G. H., Greenberg, H. B., Smith, J. L., Gregory, P. B., Merigan, T. C., Robinson, W. S. 1982; 2 (1): 39-49

    Abstract

    Fourteen chimpanzees were inoculated with pre- and posttreatment sera from seven patients with persistent hepatitis B virus infection and chronic hepatitis who had permanent responses of their infection to treatment with interferon and/or adenine arabinoside. Inoculation of pretreatment serum at a dilution of 10(-8) from a patient with a Type I response to treatment [disappearance of Dane particle DNA polymerase (DNAP) activity, HBeAg, and HBsAg from serum] resulted in infection, while undiluted posttreatment serum (all markers negative) failed to infect another animal. Pretreatment sera (DNAP, HBeAg, and HBsAg positive) from all six patients with a Type II response to treatment (disappearance of DNAP activity and HBeAg but not HBsAg from serum) led to infection in six chimpanzees after inoculation of serum dilutions varying between 10(-2) and 10(-7). Inoculation of undiluted posttreatment sera (HBsAg positive and DNAP and HBeAg negative) from the same six patients produced no evidence of hepatitis B virus infection in another six animals. These results indicate that a Type I or II response to treatment with these antiviral agents reduces the infectivity in the serum of patients with chronic hepatitis B to below the level of detection by this assay. Such changes should be useful in interrupting spread of the infection between individuals. Our findings suggest that the serum of some patients who, without treatment are HBsAg positive and DNAP and HBeAg negative, may also be free of detectable infectious hepatitis B virus.

    View details for Web of Science ID A1982NL29100006

    View details for PubMedID 6172352

  • EFFECTS OF INTERFERON-ALPHA ON HUMAN WARTS JOURNAL OF INTERFERON RESEARCH PAZIN, G. J., Ho, M., Haverkos, H. W., Armstrong, J. A., BREINIG, M. C., WECHSLER, H. L., Arvin, A., Merigan, T. C., CANTELL, K. 1982; 2 (2): 235-243

    Abstract

    Two patients with extensive warts which were stable for two years or more were treated with human interferon-alpha to assess the ability of interferon to affect this benign tumor of viral etiology. Intramuscular administration of 96.6 and 135 million units over 12-15 weeks produced softening and decreased scaling of each patient's warts. Double blind, placebo-controlled intralesional injections resulted in progressive disappearance of interferon treated warts. A dose response relationship was shown in eight warts. The minimum effective dose was 1.2 x 10(6) units injected over 15.5 weeks.

    View details for Web of Science ID A1982PG78800010

    View details for PubMedID 7119508

  • INTERFERONS AS ANTIVIRALS IN MAN PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES Merigan, T. C. 1982; 299 (1094): 109-112

    Abstract

    Interferons have now been used in both prophylaxis and treatment of a number of human viral infections. The major action has been as a prophylactic for sites within the body that are not yet involved by disease. Such a prophylactic effect can be obtained early in the treatment of acute viral infection or even during chronic viral disease. Both local and systemic prophylaxis have been achieved with regard to both respiratory and herpesviral illness. In addition, Dane particle suppression can be achieved consistently with dosages of 10(6) units or greater daily to patients with chronic hepatitis B virus infection. In certain cases with prolonged therapy there can be permanent eradication. With leucocyte-derived material of approximately 10(6) or 10(7) units per milligram protein, the major side effects have been an initial febrile response, fatigue, malaise, marrow suppression, and inhibition of hair growth. So far, side effects have been rapidly reversible on lowering of dosage. Present studies with the use of lymphoblastoid interferon and bacterial-derived interferon employ materials of significantly greater specific activity. Such experience suggests that the same general side effects that were limiting with leucocyte interferon are present with interferon produced from recombinant DNA by bacterial as well as with lymphoblastoid interferon.

    View details for Web of Science ID A1982PH78800010

    View details for PubMedID 6183684

  • THERAPEUTIC APPROACHES TO CHRONIC HEPATITIS-B PROGRESS IN LIVER DISEASES Smith, C. I., Merigan, T. C. 1982; 7: 481-494

    View details for Web of Science ID A1982RS72700028

    View details for PubMedID 6180455

  • IMMUNOREGULATION BY GAMMA-INTERFERON NATURE BASHAM, T., Merigan, T. C. 1982; 299 (5886): 778-778

    View details for Web of Science ID A1982PM85200026

    View details for PubMedID 6182471

  • INTERFERON INCREASES HLA SYNTHESIS IN MELANOMA-CELLS - INTERFERON-RESISTANT AND INTERFERON-SENSITIVE CELL-LINES PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES BASHAM, T. Y., Bourgeade, M. F., Creasey, A. A., Merigan, T. C. 1982; 79 (10): 3265-3269

    Abstract

    We report that human leukocyte interferon preparations increase the expression of beta 2-microglobulin by 100-200% on the surface of normal fibroblast and melanoma cell lines sensitive to interferon. This increase in expression can be correlated with an increase in HLA synthesis as measured by incorporation of [35S]methionine in these antigens. This enhanced HLA synthesis, which is 5- to 17-fold, is time dependent and dose related. Synchronized cells in the G0/G1 phase of the cell cycle appear to be more sensitive to this interferon action. Neither an increase in surface expression nor in HLA synthesis is observed in a melanoma cell line resistant to the antiviral and antigrowth effects of interferon. Furthermore, there appears to be a stronger correlation between this increased HLA synthesis and the antiviral function than between it and the antiproliferative action of interferon.

    View details for Web of Science ID A1982NQ31200041

    View details for PubMedID 6179079

  • ADVANCES IN INTERFERON RESEARCH WESTERN JOURNAL OF MEDICINE MARTIN, D. W., NAUGHTON, J. L., MERIGAN 1982; 136 (3): 227-235
  • RECOMBINANT LEUKOCYTE-A INTERFERON - PHARMACOKINETICS, SINGLE-DOSE TOLERANCE, AND BIOLOGIC EFFECTS IN CANCER-PATIENTS ANNALS OF INTERNAL MEDICINE GUTTERMAN, J. U., Fine, S., Quesada, J., Horning, S. J., Levine, J. F., Alexanian, R., Bernhardt, L., Kramer, M., Spiegel, H., Colburn, W., Trown, P., Merigan, T., DZIEWANOWSKI, Z. 1982; 96 (5): 549-556

    Abstract

    Sixteen patients with advanced cancer were treated with recombinant-DNA-produced pure leukocyte A interferon (IFLrA) intramuscularly in doses ranging from 3 to 198 X 10(6) units. with interval periods of 72 to 96 hours between doses. At the two lowest doses of 3 and 9 million units, there was a cross-over evaluation between IFLrA and partially pure leukocyte interferon (IFN-C) produced from human cells. THe maximum observed serum concentration of IFLrA measured by enzyme immunoassay and bioassay increased with increasing doses. The mean serum concentrations of IFLrA and IFN-C were similar. Clinical effects produced by IFLrA and IFN-C were similar, including fever, chills, myalgias, headache fatigue, and reversible leukopenia and granulocytopenia. Eight patients had transient and mild numbness of the hands or feet, or both. Three patients developed low titers of antibody to IFLrA, Seven of 16 patients showed objective evidence of tumor regression during the study.

    View details for Web of Science ID A1982NP94900001

    View details for PubMedID 6176159

  • INACTIVATION OF S-ADENOSYLHOMOCYSTEINE HYDROLASE DURING ADENINE-ARABINOSIDE THERAPY JOURNAL OF CLINICAL INVESTIGATION Sacks, S. L., Merigan, T. C., Kaminska, J., Fox, I. H. 1982; 69 (1): 226-230

    Abstract

    To assess for possible inhibition of cellular transmethylation during adenine arabinoside (ara-A) therapy, S-adenosylhomocysteine hydrolase activity was analyzed in 10 patients with chronic hepatitis B virus infection. In six patients receiving ara-A, enzyme activity was suppressed to 0-2% of control erythrocyte enzyme activity. This decrease in enzyme activity was evident within 4 h of starting the drug infusion and continued for 7 d after cessation of therapy. S-adenosylhomocysteine hydrolase activity of peripheral mononuclear cells was also measured in two patients receiving ara-A. Suppression to as low as 3.5% of pretreatment levels was found; however, marked fluctuations with partial return of enzyme activity during therapy was also observed in mononuclear cells. Inhibition of an enzyme involved in transmethylation reactions was observed in patients during ara-A therapy. This could contribute to the side effects and antiviral properties of ara-A.

    View details for Web of Science ID A1982NA38100026

    View details for PubMedID 7054240

  • VIDARABINE MONOPHOSPHATE AND HUMAN-LEUKOCYTE INTERFERON IN CHRONIC HEPATITIS-B INFECTION JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Smith, C. I., Kitchen, L. W., SCULLARD, G. H., Robinson, W. S., Gregory, P. B., Merigan, T. C. 1982; 247 (16): 2261-2265

    Abstract

    Ten young adult patients with chronic hepatitis B virus infection and positive hepatitis B e antigen and DNA polymerase (DNAP) levels were treated with alternating courses of seven to 28 days of 5 to 7.5 mg/kg of vidarabine monophosphate (adenine arabinoside monophosphate) and 28 days of human leukocyte interferon (IFN-alpha); three different regimens were given on an outpatient basis. All patients with a fall in their DNAP level, and the DNAP remained undetectable six months after treatment was stopped in one patient. The major side effect, which most often occurred in those patients receiving 7.5 mg/kg of vidarabine monophosphate, was severe muscular pains. This study demonstrated the feasibility of administering vidarabine monophosphate and interferon to outpatients. Based on data from this and other studies, it is now possible to use a relatively nontoxic regimen that includes 28 days of 5 mg/kg of vidarabine monophosphate in a larger controlled study to answer the question of efficacy.

    View details for Web of Science ID A1982NL19400022

    View details for PubMedID 6175774

  • CLINICAL AND IMMUNOLOGICAL EFFECTS OF RECOMBINANT LEUKOCYTE A INTERFERON IN 8 PATIENTS WITH ADVANCED CANCER JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Horning, S. J., Levine, J. F., MILLER, R. A., Rosenberg, S. A., Merigan, T. C. 1982; 247 (12): 1718-1722

    Abstract

    The clinical and immunologic effects of a biosynthetic human leukocyte interferon, recombinant leukocyte A interferon (IFL-rA), are reported in eight patients with advanced cancer. Single escalating doses from 3 X 10(6) units to 198 X 10(6) units were given by intramuscular injection in a phase I study. Major toxic effects included pyrexia, fatigue, myalgia, and headache. Data on the effects of IFL-rA on lymphocyte subpopulations and peripheral blood mononuclear-cell surface beta 2-microglobulin are presented. Four of eight patients had objective tumor regression, indicating that further investigation of this biologically active material is warranted.

    View details for Web of Science ID A1982NG35000017

    View details for PubMedID 6174742

  • UCLA conference. Interferon: immunobiology and clinical significance. Annals of internal medicine Stiehm, E. R., KRONENBERG, L. H., Rosenblatt, H. M., Bryson, Y., Merigan, T. C. 1982; 96 (1): 80-93

    Abstract

    Interferons are proteins elaborated by infected cells that protect noninfected cells from viral infection. These proteins produce a temporary "antiviral state" by altering nucleotide metabolism and cytoplasmic enzyme induction. Interferons appear early after viral infection locally and systematically to limit spread of viral infection; they also affect cell differentiation, growth, surface, antigen expression, morphologic findings, and immunoregulation. Several human disorders have diminished interferon production. Newborns have normal interferon alpha but deficient interferon gamma production. Infants with congenital infections may also have defects in interferon production. Immunosuppressed patients receiving transplants (marrow, heart, of kidney) have diminished interferon production, particularly immediately after transplant. Deficiencies of interferon have also been noted in Down's syndrome, cellular immunodeficiencies, uremia, malnutrition, and hematopoietic malignancy. Leukocyte interferon has been of therapeutic value in herpes zoster infections, in patients with cancer, and in patients with hepatitis B infection. Interferon has not been proved to help children with congenital cytomegalovirus or rubella. Interferon can shrink lymphoid tumors, particularly non-Hodgkin's lymphoma.

    View details for PubMedID 6172066

  • Dane particle DNA polymerase and HBeAg: impact on clinical, laboratory, and histologic findings in hepatitis B-associated chronic liver disease. Hepatology ANDRES, L. L., Sawhney, V. K., SCULLARD, G. H., Smith, J. L., Merigan, T. C., Robinson, W. S., Gregory, P. B. 1981; 1 (6): 583-585

    Abstract

    Fifty patients with chronic HBs antigenemia and Dane particle-associated DNA polymerase and HBeAg in their serum were contrasted to 46 HBsAg positive patients who had neither serum DNA polymerase or HBeAg. The time from acute onset and the duration of antigenemia were longer in patients who were DNA polymerase and HBeAg negative than in those who had both serum markers. Cirrhosis, hypoalbuminemia, and sequelae of chronic liver disease were more common in DNA polymerase, HBeAg negative patients than in those who were positive. These findings are consistent with the hypothesis that active viral replication is an early, albeit prolonged stage in the development of advanced HBsAg-associated liver disease.

    View details for PubMedID 7308991

  • From the National Institute of Allergy and Infectious Diseases. Report on a workshop on DNA recombinant technology in interferon cloning. journal of infectious diseases Dunnick, J. K., Merigan, T. C., Galasso, G. J. 1981; 143 (2): 297-300

    View details for PubMedID 6163831

  • SHORT-COURSE HUMAN-LEUKOCYTE INTERFERON IN TREATMENT OF HERPES-ZOSTER IN PATIENTS WITH CANCER ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Merigan, T. C., Gallagher, J. G., Pollard, R. B., Arvin, A. M. 1981; 19 (1): 193-195

    Abstract

    Because of encouraging results when human leukocyte interferon was given for 5 to 7 days to treat early localized herpes zoster in patients with cancer, a small placebo-controlled, randomized, double-blind trial was set up involving only 48 h of therapy. In this trial, there was no effect on acute pain or disease progression in the primary dermatome. However, a modest but significant effect was noted in that distal cutaneous spread was diminished in the treated patients compared with the controls and the treated patients had diminished severity and duration of postherpetic neuralgia. No evidence of impairment in varicella-zoster-specific lymphocyte transformation was observed in interferon-treated patients.

    View details for Web of Science ID A1981LA01400036

    View details for PubMedID 6166245

  • ANTI-VIRAL TREATMENT OF CHRONIC HEPATITIS-B VIRUS-INFECTION .1. CHANGES IN VIRAL MARKERS WITH INTERFERON COMBINED WITH ADENINE-ARABINOSIDE JOURNAL OF INFECTIOUS DISEASES SCULLARD, G. H., Pollard, R. B., Smith, J. L., Sacks, S. L., Gregory, P. B., Robinson, W. S., Merigan, T. C. 1981; 143 (6): 772-783

    Abstract

    Twenty patients with chronic active hepatitis and 12 patients with chronic persistent hepatitis associated with hepatitis B virus (HBV) infection were treated with human leukocyte interferon or adenine arabinoside alone or in combination. With interferon alone, four of 16 patients showed a permanent disappearance of HBV-associated DNA polymerase (DNAP) activity from serum. Of six patients treated with adenine arabinoside alone, only one patient became permanently DNAP-negative. With a regimen of multiple cycles of combined interferon and adenine arabinoside, seven of 16 male patients became permanently DNAP-negative. Of 69 patients who met the criteria for admission to the program, spontaneous decreases in DNAP activity without treatment were observed in only 9% during a mean observation period of 10 months. In general, patients with chronic active hepatitis, those who are female, and those with a history of recent steroid therapy responded to the antiviral agents significantly better than did the other patients.

    View details for Web of Science ID A1981MA30400003

    View details for PubMedID 6166691

  • EFFECTS OF IMMUNOSUPPRESSIVE THERAPY ON VIRAL MARKERS IN CHRONIC ACTIVE HEPATITIS-B GASTROENTEROLOGY SCULLARD, G. H., Smith, C. I., Merigan, T. C., Robinson, W. S., Gregory, P. B. 1981; 81 (6): 987-991

    Abstract

    Hepatitis B virus associated DNA polymerase activity, hepatitis b surface antigen (HBsAg), and serum aspartate aminotransferase were followed in 21 patients with chronic active hepatitis while immunosuppressive therapy (prednisone +/- azathioprine) was being withdrawn. In every case, DNA polymerase activity fell within 6-10 wk of decreasing treatment and became undetectable in 8 patients. This was usually accompanied by a fall in HbsAg titer and a transient rise in serum aspartate aminotransferase activity. Four additional patients with previously untreated HbsAg positive chronic active hepatitis were placed on prednisone for 12 wk. There was a rise in DNA polymerase activity and HBsAg titer with a fall in serum aspartate aminotransferase values during treatment. Upon discontinuing therapy, DNa polymerase activity fell dramatically in all 3 patients who completed their course of prednisone and became undetectable in 1. These findings suggest that immunosuppressive therapy has a potentiating effect on hepatitis B viral replication in patients with chronic active hepatitis.

    View details for Web of Science ID A1981MP88900002

    View details for PubMedID 7286593

  • TREATMENT OF NZB-NZW F1-HYBRID MICE WITH MYCOBACTERIUM-BOVIS STRAIN BCG OR TYPE-II INTERFERON PREPARATIONS ACCELERATES AUTOIMMUNE-DISEASE ARTHRITIS AND RHEUMATISM Engleman, E. G., Sonnenfeld, G., Dauphinee, M., Greenspan, J. S., Talal, N., McDevitt, H. O., Merigan, T. C. 1981; 24 (11): 1396-1402

    Abstract

    NZB/NZW F1 hybrid mice develop a spontaneous autoimmune disease characterized by the appearance of antinuclear antibodies and premature death due to immune complex glomerulonephritis. To investigate the possible effects of cellular immune stimulation on this disorder, groups of female NZB/NZW mice, aged 2, 5, and 7 months, were treated either with the nonspecific immunostimulatory agent Mycobacterium bovis strain BCG or with saline. Mice treated with BCG at ages 5 and 7 months died sooner than age-matched controls, and death was associated with severe glomerulonephritis, suggesting that BCG may have accelerated autoimmunity in these mice. Since BCG is known to stimulate the production of type II (or gamma) interferon, a substance with potent immunoregulatory effects, a second study was carried out to assess the effects of type II interferon on NZB/NZW disease. A greater number of type II interferon-treated mice died by 9 months of age when compared to controls, and the increased death rate was associated with a more rapid development of antinuclear antibodies and histologically confirmed glomerulonephritis. These data, together with a recent report of increases in the level of serum type II interferon in patients with active systemic lupus erythematosus, suggest that type II interferon may play a role in the pathogenesis of autoimmune disease.

    View details for Web of Science ID A1981MQ27800010

    View details for PubMedID 6172132

  • ANTIVIRAL TREATMENT OF CHRONIC HEPATITIS-B VIRUS-INFECTION - IMPROVEMENT IN LIVER-DISEASE WITH INTERFERON AND ADENINE-ARABINOSIDE HEPATOLOGY SCULLARD, G. H., ANDRES, L. L., Greenberg, H. B., Smith, J. L., Sawhney, V. K., NEAL, E. A., MAHAL, A. S., Popper, H., Merigan, T. C., Robinson, W. S., Gregory, P. B. 1981; 1 (3): 228-232

    View details for Web of Science ID A1981MP47800005

    View details for PubMedID 6169615

  • THE IMPORTANCE OF G0 IN THE SITE OF ACTION OF INTERFERON IN THE CELL-CYCLE EXPERIMENTAL CELL RESEARCH Creasey, A. A., Bartholomew, J. C., Merigan, T. C. 1981; 134 (1): 155-160

    View details for Web of Science ID A1981MA54500016

    View details for PubMedID 6166490

  • FOLLOW-UP OBSERVATIONS ON THE EFFECT OF HUMAN-LEUKOCYTE INTERFERON IN NON-HODGKINS LYMPHOMA BLOOD Louie, A. C., Gallagher, J. G., Sikora, K., Levy, R., Rosenberg, S. A., Merigan, T. C. 1981; 58 (4): 712-718

    Abstract

    Follow-up data for 11 patients with non-Hodgkin's lymphoma treated with partially purified human leukocyte interferon is presented. The interferon preparation used was 0.1% pure and treatment consisted of 5 x 10(6) U given intramuscularly twice daily for 60 injections. One complete, three partial, and three minimal responses were observed in five of seven evaluable patients with nodular non-Hodgkin's lymphoma. Duration of response appears to be from 6 to 12 mo. One patient achieved a second partial response on retreatment with interferon in spite of having received chemotherapy in the interval between interferon treatments. No responses were seen in three patients with rapidly progressive diffuse histiocytic lymphoma. Dose-limiting toxicity is leukopenia, which necessitated modification or cessation of treatment in three patients. Nonhematologic toxicities consisted of fever, malaise, arthralgia, and loss of appetite. In conclusion, interferon has activity against non-Hodgkin's lymphoma, and prior treatment with chemotherapy does not preclude a response to interferon.

    View details for Web of Science ID A1981MJ81300010

    View details for PubMedID 6168319

  • CONTROLLED CLINICAL-TRIAL OF INTRAVENOUS ACYCLOVIR IN HEART-TRANSPLANT PATIENTS WITH MUCOCUTANEOUS HERPES-SIMPLEX INFECTIONS LANCET Chou, S., Gallagher, J. G., Merigan, T. C. 1981; 1 (8235): 1392-1394

    Abstract

    Viral cultures of mucocutaneous herpes simplex lesions became negative in 5 heart-transplant patients given a 7-day course of intravenous acyclovir. Relief of pain and healing of lesions paralleled the virological response. Similar clinical and virological responses were not seen in the 5 placebo-treated patients in this double-blind placebo-controlled trial. No adverse reactions attributable to acyclovir were noted. Shedding of herpes simplex viruses recurred in 3 patients after acyclovir therapy.

    View details for Web of Science ID A1981LV00600004

    View details for PubMedID 6113353

  • VIROLOGY AND IMMUNE-MECHANISMS CANCER Merigan, T. C. 1981; 47 (5): 1091-1094

    Abstract

    Epstein-Barr virus and hepatitis B virus are two agents which chronically infect man and have been associated with specific neoplasms. Such findings point the way to new methods of control and detection of human malignancies. Furthermore, immunosuppression is another major factor underlying the development of certain malignancies in human populations. It is clear that congenital immunodeficiency states as well as organ transplant recipients requiring iatrogenic immunosuppression and cancer patients requiring chemotherapy and/or x-irradiation are susceptible to particular malignancies at a higher rate than the normal population. Such findings also provide not only clues as to the mechanisms which control tumor development but argue for certain limitations to the extent of immunosuppressive therapy utilized for treatment of cancer.

    View details for Web of Science ID A1981LF16300005

    View details for PubMedID 6263441

  • EFFECT OF TYPE-I AND TYPE-II INTERFERONS ON MURINE THYMOCYTE SURFACE-ANTIGEN EXPRESSION - INDUCTION OR SELECTION CELLULAR IMMUNOLOGY Sonnenfeld, G., Meruelo, D., McDevitt, H. O., Merigan, T. C. 1981; 57 (2): 427-439

    View details for Web of Science ID A1981LG53700015

    View details for PubMedID 6163553

  • INTERFERON ACTS DIRECTLY ON HUMAN LYMPHOCYTES-B TO MODULATE IMMUNOGLOBULIN-SYNTHESIS JOURNAL OF IMMUNOLOGY Harfast, B., HUDDLESTONE, J. R., Casali, P., Merigan, T. C., Oldstone, M. B. 1981; 127 (5): 2146-2150

    Abstract

    At different times of exposure, interferon (IFN) enhanced and suppressed pokeweed mitogen- (PWM) induced IgG synthesis by human peripheral blood lymphocytes (PBL). Pretreatment of PBL and IFN frequently increased antibody production by more than 100% when compared with that by untreated PBL. Results of experiments in which PBL were separated into T and B subpopulations indicated that IFN preparations acted directly on B cells. Thus, mixtures of IFN-treated B cells and untreated T cells from 5 of 7 persons tested produced 81% to 500% more IgG than untreated, matched control cells. However, IFN-treated monocytes mixed with untreated B and T cells or IFN-treated T cells mixed with untreated B cells failed to enhance IgG production significantly in similar assays. In contrast to the pretreatment protocol, when IFN was present in the incubation mixture throughout the PWM assay, IgG production decreased. Sephadex chromatography of the IFN and tests of the resulting fractions indicated that the IgG production-enhancing activity was located in the fraction carrying the antiviral activity.

    View details for Web of Science ID A1981MP76800081

    View details for PubMedID 6170691

  • HUMAN-LEUKOCYTE INTERFERON TREATMENT OF 2 CHILDREN WITH INSULIN DEPENDENT DIABETES DIABETOLOGIA RAND, K. H., Rosenbloom, A. L., Maclaren, N. K., Silverstein, J. H., Riley, W. J., Butterworth, B. E., Yoon, J. W., Rubenstein, A. H., Merigan, T. C. 1981; 21 (2): 116-119

    Abstract

    Two patients with newly diagnosed insulin dependent diabetes mellitus were treated with human leukocyte interferon based on the hypothesis that the diabetes was induced by an active viral infection in the pancreatic islets and could be arrested. High peak levels of serum interferon were achieved (100-200 U/ml) with minimal systemic side effects. There was no sustained therapeutic benefit as measured by increased production of endogenous insulin, or of C-peptide, or by a lower requirement for exogenous insulin. Further trials with interferon treatment should be undertaken only if evidence of active viral infection (culture, antigen detection) can be associated with insulin dependent diabetes onset and these markers followed during treatment.

    View details for Web of Science ID A1981MB58800006

    View details for PubMedID 6167482

  • THE ROLE OF HLA-DR DETERMINANTS IN MONOCYTE-MACROPHAGE PRESENTATION OF HERPES-SIMPLEX VIRUS-ANTIGEN TO HUMAN T-CELLS CELLULAR IMMUNOLOGY Stewart, G. J., Kelsall, B. L., Charron, D. J., GRUMET, F. C., Merigan, T. C. 1981; 61 (1): 11-21

    View details for Web of Science ID A1981LU49400002

    View details for PubMedID 6167367

  • Type I and type II interferons: differential antiviral actions in transformed cells. journal of general virology Bourgeade, M. F., CHANY, C., Merigan, T. C. 1980; 46 (2): 449-454

    Abstract

    In transformed mouse embryo cells, type II interferon had much less antiviral activity than type I interferon. In non-transformed cells, the two interferons had similar high activity, Reversal of the phenotype of Moloney sarcoma virus (MSV) transformed cells by sodium butyrate restored their sensitivity to the antiviral action of type II interferon. Additional evidence for a role of the cytoskeletal network in the action of type II interferon is that its antiviral effect is reduced by cytochalasin B, colchicine or vinblastine. MSV-transformed cells, selected for their resistance to the antiviral action of type I interferon, were sensitive to type II interferon. These differences in the effects of type I and II interferon on transformed cells are at present unexplained, but suggest that they have at least partially separate mechanisms of action.

    View details for PubMedID 6155431

  • CYTOMEGALO-VIRUS RETINITIS IN IMMUNOSUPPRESSED HOSTS .1. NATURAL-HISTORY AND EFFECTS OF TREATMENT WITH ADENINE-ARABINOSIDE ANNALS OF INTERNAL MEDICINE Pollard, R. B., Egbert, P. R., Gallagher, J. G., Merigan, T. C. 1980; 93 (5): 655-664

    Abstract

    Cytomegalovirus (CMV) retinitis presents with typical ophthalmologic appearance in patients with underlying immunosuppressive conditions. Fourteen patients with this disorder were diagnosed by culture of cytomegalovirus from urine or throat specimens, elevated complement fixation titers to cytomegalovirus, and characteristic funduscopic appearance. Ten of 11 had decreased CMV-specific cell-mediated immune responses. Three of seven who received no specific therapy improved after decreasing dosages of immunosuppressive drugs. Seven patients with progressive disease despite minimal immunosuppressive therapy were treated with adenine arabinoside at doses from 1 to 20 mg/kg of body weight per day. Daily dosages of 20 mg/kg . d in five patients were associated with decreased inflammatory activity and improvement of retinal lesions and quantitative decreases in urinary virus excretion. Adenine arabinoside administration was associated with significant gastrointestinal, hematologic, and neurologic side effects. Adenine arabinoside may have some beneficial effect on selected patients with progressive CMV retinitis.

    View details for Web of Science ID A1980KQ78400001

    View details for PubMedID 6259979

  • EFFECT OF INTERFERON THERAPY ON CIRCULATING LYMPHOCYTES IN HUMANS JOURNAL OF INTERFERON RESEARCH Rasmussen, L., Merigan, T. C. 1980; 1 (1): 101-110

    Abstract

    The effect of interferon treatment on both lymphocyte subpopulation numbers and function was studied in two groups of patients who were being treated systemically with 0.5 to 1.0 x 10(7) units of human leukocyte-derived interferon (HulFN-alpha) daily. Patients with nodular lymphocytic, poorly differentiated non-Hodgkin's lymphoma (NLPD) were given interferon for 30 days and those with chronic hepatitis B infection were treated in cycles for 4 to 7 days. In both patient groups, B lymphocytes numbers were reduced during treatment, but T lymphocyte numbers were unaffected. T lymphocyte responses, measured by blast transformation to herpesvirus antigens were generally low before treatment in NLPD patients. The responses were restored after termination of therapy. In two NLPD patients given two courses of treatment separated by a 3 month interval, the restored T lymphocyte responses were inhibited during the second course of treatment. In patients with chronic hepatitis B virus infection, lymphocyte blast transformation to the viral antigens were also depressed during treatment compared to pretreatment responses. Changes in lymphocyte responses to phytohemagglutinin and pokeweed mitogen were not observed in either patient group.

    View details for Web of Science ID A1980LN41600013

    View details for PubMedID 6180033

  • CYTOMEGALO-VIRUS RETINITIS IN IMMUNOSUPPRESSED HOSTS .2. OCULAR MANIFESTATIONS ANNALS OF INTERNAL MEDICINE Egbert, P. R., Pollard, R. B., Gallagher, J. G., Merigan, T. C. 1980; 93 (5): 664-670

    Abstract

    We observed the course of cytomegalovirus (CMV) retinitis in 21 eyes of 14 immunosuppressed patients. In two patients, other organisms, specifically Toxoplasma and Candida, also appeared to be causing retinal disease simultaneously. Post-mortem examination was done on 10 eyes from seven patients. At initial presentation, the retinitis was often asymptomatic and diagnosed during routine examination. The ophthalmoscopic picture was characteristic of cytomegalovirus; the early lesion was a small opaque, white granular area of retinal necrosis that spread in a centrifugal, brush-fire-like manner over 1 to 8 months. Vessel sheating and hemorrhages appeared as the disease progressed. In two patients new foci of retinitis developed remote from the original lesion. Four weeks to 4 months (average, 10 weeks) elapsed from the most extensive disease to total resolution. Resolution of active disease left a subtle retinal scar, and final visual acuity was reduced in one half the eyes. Repeated ophthalmoscopic examinations can aid in early diagnosis of CMV retinitis and in ascertaining which persons are most at risk for visual loss.

    View details for Web of Science ID A1980KQ78400002

    View details for PubMedID 6259980

  • Does human leukocyte interferon influence the restriction point control in cultured cells? Annals of the New York Academy of Sciences Creasey, A. A., Bartholomew, J. C., Merigan, T. C. 1980; 350: 208-210

    View details for PubMedID 6165275

  • CELLULAR AND HUMORAL IMMUNITY IN THE PATHOGENESIS OF RECURRENT HERPES VIRAL-INFECTIONS IN PATIENTS WITH LYMPHOMA JOURNAL OF CLINICAL INVESTIGATION Arvin, A. M., Pollard, R. B., Rasmussen, L. E., Merigan, T. C. 1980; 65 (4): 869-878

    Abstract

    86 patients with lymphoma were evaluated prospectively for clinical and laboratory evidence of recurrent varicella-zoster, herpes simplex, and cytomegalovirus infections during the first 16 mo of treatment. Cellular immunity to the viral antigens was measured by in vitro lymphocyte transformation and interferon production. Antibody titers and nonspecific measures of cellular immunity, including T-cell quantitation and transformation to phytohemagglutinin, were also assessed. The patients treated with radiation and chemotherapy had the highest incidence of reactivation of each of the viruses (15-19%). Greater susceptibility to herpes viral reactivation in these patients correlated with suppression of cell-mediated immunity to the specific virus. In individual patients, suppression of cellular immunity to the specific herpes viral antigen preceded each episode of reactivation, but recurrent infection did not occur in all patients with diminished specific lymphocyte transformation. Absence of the response appears to be a necessary but not a sufficient condition for the recrudescence of latent infection. Better preservation of cellular immunity to herpes simplex antigen during treatment was associated with infrequent reactivation of herpes simplex. In 25 patients with acute herpes zoster, uncomplicated recovery from the infection was accompanied by the development of lymphocyte transformation and interferon production to varicella-zoster antigen. Quantitation of T-cell numbers and phytohemagglutinin transformation did not correlate with the presence of viral cellular immunity in treated patients. Responses returned while T-cell numbers were low, and the recovery of phytohemagglutinin transformation often preceded recovery of the responses to viral antigens. Although some patients had deficiencies in viral cellular immunity at diagnosis, the duration of the suppression of specific antiviral responses resulting from treatment appears to be the most important factor predisposing to the recurrence of herpes infections in lymphoma patients.

    View details for Web of Science ID A1980JP40100013

    View details for PubMedID 6244336

  • INTERFERON IN CHRONIC HEPATITIS-B INFECTION LANCET Merigan, T. C., Robinson, W. S., Gregory, P. B. 1980; 1 (8165): 422-423

    View details for Web of Science ID A1980JF46200031

    View details for PubMedID 6101871

  • INHIBITION OF LYMPHOMA HYBRIDS BY HUMAN INTERFERON LANCET Sikora, K., Dilley, J., Merigan, T., BASHAM, T., Levy, R. 1980; 2 (8200): 891-893

    Abstract

    A set of stable mouse-human hybrids was constructed from the neoplastic lymphocytes from a patient with nodular lymphoma and from another with chronic lymphocytic leukaemia. Both patients had shown a clinical response to human leucocyte interferon. The same interferon preparation inhibited the growth rate of 14 out of 17 established hybrid cell lines. This system provides evidence of a direct growth inhibitory effect of interferon on neoplastic B lymphocytes. Such a system could be used to predict the sensitivity of a patient's tumour before therapy.

    View details for Web of Science ID A1980KM63500007

    View details for PubMedID 6159511

  • ROLE OF G0-G1 ARREST IN THE INHIBITION OF TUMOR-CELL GROWTH BY INTERFERON PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES Creasey, A. A., Bartholomew, J. C., Merigan, T. C. 1980; 77 (3): 1471-1475

    Abstract

    We report here that human leukocyte interferon preparations are capable of influencing the transition of human melanoma cells from the "A" state to the "B" phase. Human melanoma cells that enter a quiescent stage at high cell density are more sensitive to the cytostatic action of interferon than those that continue to proliferate under similar conditions. Cell cycle perturbations caused by interferon in these cells include a decreased transition rate out of G0-G1 ("A" state) into S ("B" phase) and a prolongation of S. These findings support the idea that some metabolic event is required for progress through the G0-G1 phase of the cell cycle and is susceptible to interferon action.

    View details for Web of Science ID A1980JL81400046

    View details for PubMedID 6154934

  • CLINICAL VIROLOGY, INTERFERON, AND INFECTIOUS-DISEASES IN THE PEOPLES-REPUBLIC-OF-CHINA IN 1979 JOURNAL OF INFECTIOUS DISEASES Merigan, T. C. 1980; 141 (2): 265-270

    View details for Web of Science ID A1980JN37400022

    View details for PubMedID 6154113

  • ZOSTER IMMUNE GLOBULIN PROPHYLAXIS OF DISSEMINATED ZOSTER IN COMPROMISED HOSTS - RANDOMIZED TRIAL ARCHIVES OF INTERNAL MEDICINE Stevens, D. A., Merigan, T. C. 1980; 140 (1): 52-54

    Abstract

    Herpes zoster can be a severe, and sometimes fatal, virus infection in its disseminated form in immunocompromised hosts. Previous studies have suggested that delay in appearance of antibody to varicella-zoster virus occurs as one defect in such patients. In this study, pooled gamma-globulin (normal serum globulin [NSG]) and zoster immune globulin ([ZIG] prepared from convalescent zoster patients) were compared for their ability to prevent dissemination of early localized zoster in immunocompromised hosts. Either agent was given intramuscularly in randomized double-blind fashion within nine days of onset of zoster in 97 patients. Despite greater than 100-fold differences in titer of anti-varicella-zoster virus antibody, ZIG did not appear superior to NSG in prophylaxis of dissemination or diminishing postherpetic pain in zoster in immunocompromised hosts. Zoster immune globulins should be reserved for prophylaxis and modification of varicella, where its beneficial effect has been demonstrated.

    View details for Web of Science ID A1980JC99800009

    View details for PubMedID 6153260

  • TOXICITY OF VIDARABINE JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Sacks, S. L., Smith, J. L., Pollard, R. B., Sawhney, V., MAHOL, A. S., Gregory, P., Merigan, T. C., Robinson, W. S. 1979; 241 (1): 28-29

    View details for Web of Science ID A1979GC29900007

    View details for PubMedID 758490

  • INVITRO PRODUCTION AND CELLULAR-ORIGIN OF MURINE TYPE-II INTERFERON IMMUNOLOGY Sonnenfeld, G., MANDEL, A. D., Merigan, T. C. 1979; 36 (4): 883-890

    Abstract

    Antigen-specific type II interferon was produced in vitro by harvesting supernatants of spleen cell cultures from Swiss-Webster mice sensitized with Mycobacterium bovis strain BCG and challenged with old tuberculin. Treatment of C3H mouse spleen cell cultures with appropriate anti-Ia, anti-IgG, anti-Thy-1 or anti-Ly-2,3 sera resulted in a significant decrease in production of type II interferon. Removal of nylon wool adherent cells or cells with histamine receptors by column chromatography similarly caused reduced production of type II interferon. Recombination of spleen cell cultures treated with anti-Ia and anti-Thy-1 sera or of cells treated with anti-IgG and anti-Thy-1 resulted in restored production of type II interferon. Interferon production was also restored by combination of cells passed through histamine columns with anti-Ia treated cells, or those passed through nylon wool columns with anti-Thy-1 treated cells. Anti-Ly-1 serum treatment had no effect on interferon production. Removal of plastic-adherent cells or cells that had phagocytosed carbonyl iron also decreased interferon production, suggesting that macrophages were also involved in type II interferon production. Recombination of non-adherent spleen cells with anti-Ia and anti-Thy-1 sera treated spleen cells, however, did not restore interferon production, suggesting that other cells in addition to macrophages are depleted by the adherence procedure. These findings indicate that type II interferon is produced by suppressor or cytotoxic (Ly-2,3+) T lymphocytes in co-operation with one or two additional cell types: (i) B lymphocytes, and (ii) macrophages.

    View details for Web of Science ID A1979GR11400033

    View details for PubMedID 374263

  • A regulatory role for interferon in immunity. Annals of the New York Academy of Sciences Sonnenfeld, G., Merigan, T. C. 1979; 332: 345-355

    View details for PubMedID 231406

  • NATURAL KILLING IN ESTROGEN-TREATED MICE RESPONDS POORLY TO POLY-I.C DESPITE NORMAL STIMULATION OF CIRCULATING INTERFERON JOURNAL OF IMMUNOLOGY Seaman, W. E., Merigan, T. C., Talal, N. 1979; 123 (6): 2903-2905

    Abstract

    Natural killing by mouse spleen cells can be stimulated in vivo by interferon or by agents that stimulate interferon, such as poly I.C. Natural killing can be suppressed in vivo by the sustained administration of 17 beta-estradiol. In BALB/c mice that had been treated with 17 beta-estradiol for 10 weeks, natural killing did not respond to intravenous poly I.C, although stimulation of circulating interferon was equal to controls. Estradiol, then, does not block interferon production but does suppress the response of natural killer cells to interferon. It is suggested that estrogens either block the maturation of natural killer cells or reduce the number of natural killer cell precursors.

    View details for Web of Science ID A1979HU90100072

    View details for PubMedID 227961

  • SUPPRESSIVE EFFECT OF INTERFERON ON ERYTHROID CELL-PROLIFERATION EXPERIMENTAL HEMATOLOGY Ortega, J. A., Ma, A., Shore, N. A., Dukes, P. P., Merigan, T. C. 1979; 7 (3): 145-150

    Abstract

    The effect of interferon on mouse and human in vitro erythropoiesis was investigated using the mouse marrow CFU-E and the human blood BFU-E systems, respectively. Homologous interferons were found to have a marked inhibitory effect on mouse CFU-E and human BFU-E proliferation. This inhibitory effect was dose related and independent of the erythropoietin concentration used. The effective concentration of human interferon was within the range observed in humans following viral infections. It is suggested that interferon may play a role in the mechanism of the acute erythroblastopenic crisis observed at times in patients with chronic anemia following viral infections.

    View details for Web of Science ID A1979GW50900004

    View details for PubMedID 446582

  • PATIENT FACTORS CONTRIBUTING TO THE EMERGENCE OF GENTAMICIN-RESISTANT SERRATIA-MARCESCENS AMERICAN JOURNAL OF MEDICINE Yu, V. L., OAKES, C. A., AXNICK, K. J., Merigan, T. C. 1979; 66 (3): 468-472

    Abstract

    One hundred forty nosocomial Serratia marcescens infections (including 76 cases of bacteremia) were identified by prospective surveillance from 1975 through 1977 and retrospective chart review from 1968 through 1974. Thirty-four cases (24 per cent) involved gentamicin-resistant strains. All gentamicin-resistant strains appeared after 1974. Ninety per cent of the patients had undergone surgery, and 88 per cent had received prior antimicrobial therapy. The emergence of gentamicin-resistant S. marcescens paralleled the increase in usage of gentamicin. Prior use of gentamicin for more than two days in an individual patient was a significant risk factor (P = 0.0002) for being infected with a Serratia that was gentamicin-resistant. Other factors which separated gentamicin-resistant Serratia infections from gentamicin-sensitive Serratia infections were (1) urinary site of infection (P = 0.0005), (2) urinary catheter (P = 0.002), (3) endotracheal tube or tracheotomy (P = 0.03) and (4) increasing duration of hospitalization (P less than 0.05). Thirty-three of 34 (97 per cent) patients with gentamicin-resistant strains had urinary catheters. Specific measures to control infection were effective in decreasing the incidence of infections caused by gentamicin-resistant Serratia.

    View details for Web of Science ID A1979GP21100021

    View details for PubMedID 373434

  • NOSOCOMIAL VARICELLA .1. OUTBREAK IN ONCOLOGY PATIENTS AT A CHILDRENS HOSPITAL WESTERN JOURNAL OF MEDICINE Meyers, J. D., Merigan, T. C., JENNISON, M. H. 1979; 130 (3): 196-199

    Abstract

    Twenty cases of varicella occurred in patients or siblings of patients in a 41-day period in a children's hospital. Most cases were among oncology patients, with transmission occurring in both the inpatient and outpatient areas. One patient died after visceral dissemination of varicella. Neither pooled immunoglobulin nor zoster immune plasma was effective in preventing clinical varicella, although zoster immune plasma appeared to ameliorate the illness. Recommended control measures included strict isolation or discharge of infected patients, and respiratory isolation or discharge of exposed susceptibles. Although apparently too late to be effective in this outbreak, similar measures are warranted should nosocomial outbreaks of varicella occur elsewhere.

    View details for Web of Science ID A1979GQ05100002

    View details for PubMedID 425501

  • INDUCTION AND KINETICS OF NATURAL KILLER CELLS IN HUMANS FOLLOWING INTERFERON THERAPY NATURE HUDDLESTONE, J. R., Merigan, T. C., Oldstone, M. B. 1979; 282 (5737): 417-419

    Abstract

    Natural killer (NK) cells are non-B, non-T lymphocytes that effect spontaneous cytolysis of both virus-infected and neoplastically transformed target cells. These NK lymphocytes have been detected in several species including man. Interferon is a primary regulator of natural killer activity. Because NK cells have been implicated in the regulation of tumour cell expression and can be induced by interferon in murine models, we have studied patients receiving large doses of interferon to determine (1) whether interferon could induce NK lymphocytes in the peripheral blood of man, and (2) whether there are characteristic kinetics for the appearance, disappearance and reactivation of NK lymphocytes following interferon therapy. We report here the activation of human NK cells by the systemic inoculation of human subjects with interferon. Five patients received interferon as therapy for non-Hodgkin's lymphoma. All showed a marked increase in NK cell activity 12--24 h after inoculation. Peak NK activity occurred 18 h after introducing interferon, and thereafter declined rapidly but remained above pre-interferon levels. Induced NK activity occurred with reintroduction of interferon but at lower levels of activity and with different kinetics.

    View details for Web of Science ID A1979HU92100054

    View details for PubMedID 503223

  • EFFECTS OF INTERFERON AND ADENINE-ARABINOSIDE TREATMENT OF HEPATITIS-B VIRUS-INFECTION ON CELLULAR IMMUNE-RESPONSES ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Hafkin, B., Pollard, R. B., Tiku, M. L., Robinson, W. S., Merigan, T. C. 1979; 16 (6): 781-787

    Abstract

    Fifteen patients with chronic hepatitis B were treated with adenine arabinoside (Ara-A) or human leukocyte interferon (HLI). Cellular immune response to hepatitis B virus surface antigen and antigens prepared from herpes simplex virus, varicella zoster virus, and cytomegalovirus was measured by a lymphocyte blast transformation assay and an assay for interferon production. Measurements were made before, during, and after antiviral treatment. Unlike patients convalescing from acute hepatitis B, only 2 of 15 patients with chronic hepatitis B had significant blast transformation to hepatitis B surface antigen. One such response occurred during the pretreatment period of HLI therapy, and the other was in a patient undergoing low-dose (<10(5) U/kg per day) HLI therapy. Mononuclear cell cultures were tested for interferon production in the presence of hepatitis B surface antigen. Cells from only 1 of 15 patients produced detectable levels of interferon. In contrast, all of these patients had normal cellular immune responses to herpesvirus antigens. Transformation responses to herpes antigens decreased three- to fivefold after patients were treated with >10(5) U of HLI per kg per day. Antiviral therapy with <10(5) U of HLI per kg per day or Ara-A did not produce a detectable depression of transformation response. Ara-A produced marked lymphocytopenia and a marked lymphocyte fragility after 5 or more days of therapy. In vitro Ara-A was toxic to lymphocytes at concentrations as low as 0.5 mug/ml. These changes in lymphocyte parameters may affect the outcome of antiviral therapy.

    View details for Web of Science ID A1979JE30900015

    View details for PubMedID 533259

  • HUMAN INTERFERON AS A THERAPEUTIC AGENT NEW ENGLAND JOURNAL OF MEDICINE Merigan, T. C. 1979; 300 (1): 42-43

    View details for Web of Science ID A1979GC50200012

    View details for PubMedID 758162

  • PROLONGED HERPES-ZOSTER INFECTION ASSOCIATED WITH IMMUNOSUPPRESSIVE THERAPY ANNALS OF INTERNAL MEDICINE Gallagher, J. G., Merigan, T. C. 1979; 91 (6): 842-846

    Abstract

    Unusually prolonged zoster was observed in four patients, two with cardiac transplants, one with acute lymphocytic leukemia, and one with diffuse histiocytic lymphoma. Lesions increased in number and persisted for 5 to 24 weeks before beginning to resolve. Specific cellular-immune responsiveness to varicella-zoster virus was markedly depressed during these infections. Absolute numbers of T lymphocytes were also very low. Reducing immunosuppressive therapy to increase immune responses appeared to initiate resolution of zoster lesions and halt dissemination. In one patient treatment with adenine arabinoside was also needed for resolution of disseminated zoster. This syndrome appears to be counterpart of the prolonged mucocutaneous herpes-simplex infection previously reported in immunosuppressed cardiac and renal transplant patients.

    View details for Web of Science ID A1979HY33200006

    View details for PubMedID 391116

  • SELECTIVE IMPAIRMENT OF LYMPHOCYTE-REACTIVITY TO VARICELLA-ZOSTER VIRUS-ANTIGEN AMONG UNTREATED PATIENTS WITH LYMPHOMA JOURNAL OF INFECTIOUS DISEASES Arvin, A. M., Pollard, R. B., Rasmussen, L. E., Merigan, T. C. 1978; 137 (5): 531-540

    Abstract

    Herpes zoster is a frequent complication of lymphoreticular malignancy. In this study two assays of in vitro cellular immune response to varicella-zoster virus (VZV) antigen, lymphocyte transformation and interferon production, were performed in normal subjects with recent and remote VZV infection. The responses of patients with lymphoma were measured before treatment and during long-term remission and then compared with those of normal subjects. Despite levels of antibody to VZV that were equivalent to those in normal subjects, 44% of the untreated lymphoma patients showed a lower transformation response to VZV antigen than the normal patients. Production of interferon in response to VZV antigen was absent in 32% of the untreated patients. In contrast, lymphocyte responses in untreated patients to herpes simplex virus antigen were within the range observed in a normal population. Interferon production by lymphocytes in response to cytomegalovirus antigen was also lower among untreated lymphoma patients than among normal patients, but lymphocyte transformation was not. Twenty-two percent of lymphoma patients in long-term remission continued to have diminished cellular immune responses to VZV antigen. Observations in these patient populations and in normal subjects with acute herpes zoster suggest that deficiencies in in vitro lymphocyte responses may correlate with increased susceptibility to clinical infection with VZV.

    View details for Web of Science ID A1978EZ28600004

    View details for PubMedID 207782

  • HUMAN LEUKOCYTE INTERFERON IN TREATMENT OF VARICELLA IN CHILDREN WITH CANCER - PRELIMINARY CONTROLLED TRIAL ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Arvin, A. M., Feldman, S., Merigan, T. C. 1978; 13 (4): 605-607

    Abstract

    Eighteen patients who developed varicella while being treated for malignancy received human leukocyte interferon in a randomized double-blind placebo-controlled trial. Complications of varicella occurred in six of nine placebo recipients, but in only two of nine interferon recipients. Interferon was tolerated without significant side effects.

    View details for Web of Science ID A1978EW79300009

    View details for PubMedID 352259

  • ROLE OF LYMPHOCYTES-T IN CELLULAR IMMUNE-RESPONSES DURING HERPES-SIMPLEX VIRUS-INFECTION IN HUMANS PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Rasmussen, L., Merigan, T. C. 1978; 75 (8): 3957-3961

    Abstract

    Lymphocyte blast transformation and interferon production in mononuclear cell culture prepared on Ficoll-Hypaque gradients from individuals with herpes simplex virus-I infection were enhanced by a disease recurrence. Responses to both herpes simplex virus-2 and phytohemagglutinin were unaltered. Transformation to herpes simplex virus-I antigen was adversely affected by depleting either thymus-derived (T) lymphocytes or bone marrow-derived (B) lymphocytes together with monocytes from cultures. The transformation response was reconstructed when the selectively depleted lymphocyte populations were recombined. X-irradiation of either T or B lymphocytes and monocytes showed that T lymphocytes incorporated [3H]thymidine with the aid of a radioresistant non-rosetting cell, probably a monocyte. Depletion of B lymphocytes and monocytes, but not of T lymphocytes, resulted in reduction in interferon production. Irradiated B lymphocytes and monocytes failed to produce significant quantities of interferon, suggesting that a radiosensitive B cell was a major interferon source.

    View details for Web of Science ID A1978FN26200091

    View details for PubMedID 308659

  • HUMAN LEUKOCYTE INTERFERON FOR TREATMENT OF HERPES-ZOSTER IN PATIENTS WITH CANCER NEW ENGLAND JOURNAL OF MEDICINE Merigan, T. C., RAND, K. H., Pollard, R. B., ABDALLAH, P. S., Jordan, G. W., FRIED, R. P. 1978; 298 (18): 981-987

    Abstract

    We tested the effect of human leukocyte interferon on early localized herpes zoster infections in three placebo-controlled, randomized double-blind trials involving 90 patients with cancer. There were no significant differences in pretreatment severity of infection or nature of underlying disease in the groups. Higher dosages of more purified interferon in the second and third trials produced a significant (P less than or equal to 0.01) decrease in cutaneous dissemination. No dissemination occurred in those receiving the highest dosage (5.1 x 10(5) U per kilogram per day) (P less than or equal to 0.025). The number of days of new-vesicle formation in the primary dermatome decreased (mean, 2.3 days, P less than or equal to 0.05) in this group. Treated patients had a trend toward less acute pain, and significantly (P less than or equal to 0.05) diminished severity of post-herpetic neuralgia, at the two highest dosage levels. Visceral complications were six times less frequent in interferon recipients. High-dosage interferon appeared effective in limiting cutaneous dissemination, visceral complications and progression within the primary dermatome.

    View details for Web of Science ID A1978EW86500001

    View details for PubMedID 347294

  • TIME AND DOSAGE DEPENDENCE OF IMMUNOENHANCEMENT BY MURINE TYPE-II INTERFERON PREPARATIONS CELLULAR IMMUNOLOGY Sonnenfeld, G., MANDEL, A. D., Merigan, T. C. 1978; 40 (2): 285-293

    View details for Web of Science ID A1978FV41700004

    View details for PubMedID 363280

  • CYTOMEGALOVIRUS - NOT SO INNOCENT BYSTANDER JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION RAND, K. H., Merigan, T. C. 1978; 240 (22): 2470-2471

    View details for Web of Science ID A1978FW86400025

    View details for PubMedID 213621

  • FACTORS AFFECTING INTERFERON SENSITIVITY OF HUMAN CYTOMEGALOVIRUS INTERVIROLOGY Holmes, A. R., Rasmussen, L., Merigan, T. C. 1978; 9 (1): 48-55

    Abstract

    Several factors affected the interferon sensitivity of human cytomegalovirus in human foreskin fibroblast cultures. An inoculum of infected cells was up to 300-fold less sensitive than a cell-free inoculum of equivalent input multiplicity. A 10-fold increase in the dose of infectious units of either type of inoculum was associated with a 10-fold or greater decrease in interferon sensitivity. Several aspects of the virus-cell interaction were examined and parameters indicative of cell infection were less inhibited by interferon than were those for virus replication.

    View details for Web of Science ID A1978DZ93400006

    View details for PubMedID 202571

  • CELL-MEDIATED-IMMUNITY TO CYTOMEGALOVIRUS-INFECTION IN NORMAL SUBJECTS AND CARDIAC TRANSPLANT PATIENTS JOURNAL OF INFECTIOUS DISEASES Pollard, R. B., RAND, K. H., Arvin, A. M., Merigan, T. C. 1978; 137 (5): 541-549

    Abstract

    Two assays of cell-mediated immunity, lymphocyte transformation and interferon production, were adapted to test for specific immunity to cytomegalovirus (CMV). Normal individuals seropositive for CMV had a mean transformation index of 7.9 in response to antigen of the Davis strain of CMV, whereas all of 14 seronegative normal individuals had transformation indexes of less than or equal to 3.0. Interferon production in seropositive and seronegative individuals was not statistically different. One to two months after CMV mononucleosis (after the termination of viruria), normal individuals had increased transformation indexes. Recipients of cardiac transplants within six months after transplant had normal levels of antibody to CMV; lymphocyte transformation and interferon production in these subjects were markedly decreased and returned to normal by three years and between one and three years after transplant, respectively. A syndrome of unexplained fever, hepatitis, pneumonitis, leukopenia, and atypical lymphocytes was common in a group of recipients with primary CMV infection. Shedding of virus was frequent in these symptomatic patients and in patients with repeat infection during the first three years after transplant. These assays appear to identify periods of immune deficits correlating with increased incidence of infection with CMV.

    View details for Web of Science ID A1978EZ28600005

    View details for PubMedID 207783

  • Lymphocyte transformation and interferon production as measures of cellular immunity in lymphoma patients. IARC scientific publications Arvin, A. M., Pollard, R. B., Rasmussen, L. E., RAND, K. H., Merigan, T. C. 1978: 745-751

    Abstract

    Our studies of in vitro cellular immune responses to herpesviruses have shown that, before treatment, lymphoma patients have decreased transformation to varicella-zoster virus antigen compared to herpes simplex virus and cytomegalovirus antigens. Interferon production to varicella-zoster virus and cytomegalovirus antigens is also decreased. During the first six months of treatment, decreased lymphocyte transformation and interferon production to all herpesviral antigens was observed. Among patients in long-term remission, recovery from the suppression associated with treatment was noted except that interferon production to varicella-zoster virus antigen remained decreased.

    View details for PubMedID 221398

  • PRELIMINARY-OBSERVATIONS ON EFFECT OF HUMAN LEUKOCYTE INTERFERON IN NON-HODGKINS LYMPHOMA NEW ENGLAND JOURNAL OF MEDICINE Merigan, T. C., Sikora, K., BREEDEN, J. H., Levy, R., Rosenberg, S. A. 1978; 299 (26): 1449-1453

    View details for Web of Science ID A1978GC17400008

    View details for PubMedID 362211

  • PERSPECTIVES FOR CONTROL OF CYTOMEGALOVIRUS INFECTIONS IN BONE-MARROW TRANSPLANT RECIPIENTS TRANSPLANTATION PROCEEDINGS Pollard, R. B., Merigan, T. C. 1978; 10 (1): 241-245

    View details for Web of Science ID A1978ES53400044

    View details for PubMedID 205021

  • EFFECT OF VIDARABINE ON CHRONIC HEPATITIS-B VIRUS-INFECTION JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Pollard, R. B., Smith, J. L., NEAL, E. A., Gregory, P. B., Merigan, T. C., Robinson, W. S. 1978; 239 (16): 1648-1650

    View details for Web of Science ID A1978EV02700017

    View details for PubMedID 633577

  • Prospects for control of herpesvirus-related diseases: a review. IARC scientific publications Merigan, T. C., RAND, K. H. 1978: 947-963

    View details for PubMedID 221415

  • INCREASED PULMONARY SUPER-INFECTIONS IN CARDIAC-TRANSPLANT PATIENTS UNDERGOING PRIMARY CYTOMEGALOVIRUS-INFECTION NEW ENGLAND JOURNAL OF MEDICINE RAND, K. H., Pollard, R. B., Merigan, T. C. 1978; 298 (17): 951-953

    View details for Web of Science ID A1978EV91400005

    View details for PubMedID 205784

  • Multiplicity-dependent replication of varicella-zoster virus in interferon-treated cells. journal of general virology Rasmussen, L., Holmes, A. R., HOFMEISTER, B., Merigan, T. C. 1977; 35 (2): 361-368

    Abstract

    The inhibitory effects of interferon (IF) on the replication of varicella-zoster (VZ) virus in human foreskin fibroblast (HFF) cultures inoculated with infected cells or with cell-free virus were assayed by measuring (1) yields of infected cells, (2) plaques, (3) microfoci and (4) cytopathic effects. More IF was needed to reduce yields of infected cells at high input multiplicities of challenge than at low input multiplicites, and still more IF was needed to prevent cytopathology due to VZ virus. A cell-free virus inoculum was more sensitive to the inhibitory effects of IF than an inoculum of infected cells. With the latter, but not with cell-free virus, the continuous presence of IF in the medium was necessary for it to express its maximum antiviral activity. To explain these results, it is suggested that some herpesviruses may establish "reservoirs' of infectivity and thus provide a prolonged challenge to IF-treated cells which are not uniformly resistant to infection.

    View details for PubMedID 195010

  • PHARMACOKINETICS AND SIDE-EFFECTS OF INTERFERON IN MAN TEXAS REPORTS ON BIOLOGY AND MEDICINE Merigan, T. C. 1977; 35: 541-547

    View details for Web of Science ID A1977FC98200077

    View details for PubMedID 358475

  • CELLULAR IMMUNITY AND HERPESVIRUS INFECTIONS IN CARDIAC-TRANSPLANT PATIENTS NEW ENGLAND JOURNAL OF MEDICINE RAND, K. H., Rasmussen, L. E., Pollard, R. B., Arvin, A., Merigan, T. C. 1977; 296 (24): 1372-1377

    Abstract

    We observed severe infection with herpes simplex virus in cardiac-transplant patients despite their high serum antibody levels to this virus. Therefore, we sought to correlate clinical susceptibility to two herpesvirus (simplex and zoster) infections with specific cellular immunity, assessed by the transformation and interferon responses of peripheral blood mononuclear cells to heat-inactivated antigens. Transformation and interferon response to herps simplex virus was maximally depressed immediately after transplantation, the time when severe and prolonged infection with herps simplex virus occurred. Six months to six years after transplantation, both clinical susceptibility and cellular immunity to herpes simplex virus were normal. Herpes zoster infections were more frequent than normal at all times after cardiac transplantation; depressed or absent cellular responses to the varicella zoster virus paralleled that susceptibility. In these patients the risk of severe herpesvirus infections correlated with depressed cellular immune responses to the specific viral agent involved.

    View details for Web of Science ID A1977DJ32700002

    View details for PubMedID 193008

  • ADENINE-ARABINOSIDE IN TREATMENT OF PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY - USE OF VIRUS-CONTAINING CELLS IN URINE TO ASSESS RESPONSE TO THERAPY ANNALS OF NEUROLOGY RAND, K. H., Johnson, K. P., Rubinstein, L. J., Wolinsky, J. S., Penney, J. B., Walker, D. L., PADGETT, B. L., Merigan, T. C. 1977; 1 (5): 458-462

    Abstract

    Two patients with biopsy-proved progressive multifocal leukoencephalopathy (PML) were treated with near-maximal doses of adenine arabinoside (Ara-A), 18.6 and 20 mg per kilogram of body weight per day for 14 days. In both patients, clinical progression of the disease was correlated with an increase in the size of low-density lesions seen by computerized tomography. One of the patients was observed to excrete abnormal epithelial cells into the urine. These cells contained papovaviruslike particles, and JC virus was cultured from the urine sediment. The relative number of these abnormal cells declined during Ara-A treatment. Both patients died shortly after the conclusion of therapy without a change in the progression of the central nervous system disease. Systemic administration of Ara-A did not offer significant clinical benefit in the treatment of these 2 advanced cases of PML.

    View details for Web of Science ID A1977DJ31400008

    View details for PubMedID 214020

  • INHIBITION OF MULTIPLICATION OF MYCOBACTERIUM-LEPRAE BY POLYINOSINIC-POLYCYTIDYLIC ACID ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Levy, L., Merigan, T. C. 1977; 11 (1): 122-125

    Abstract

    Contrary to the results of an earlier study in which polyinosinic-polycytidylic acid [poly(I:C)] administered intraperitoneally to mice had no effect on multiplication of Mycobacterium leprae in the mouse footpad, the local administration of poly(I:C) every 12 h for 15 doses during logarithmic multiplication was found both to inhibit bacterial multiplication and to produce high tissue levels of interferon (IF). Local administration of poly(I) alone inhibited multiplication of M. leprae to almost as great a degree without at the same time producing a measurable IF titer in the footpad tissues. Mouse IF and "mock" IF both inhibited bacterial multiplication to the same degree, but administration of only the former resulted in a measurable IF titer. Polyadenylic-polyuridylic acid administered locally neither inhibited multiplication nor induced IF; fetal calf serum, administered in the same concentration as found in the preparations of IF and mock IF, was modestly inhibitory, without inducing IF. Thus, the local administration of poly(I:C) appears to have inhibited multiplication of M. leprae independently of IF induction.

    View details for Web of Science ID A1977CS79700023

    View details for PubMedID 319745

  • INTERFERON INHIBITION OF LYMPHOCYTE MITOGENESIS IMMUNOLOGY Weinstein, Y., Brodeur, B. R., Melmon, K. L., Merigan, T. C. 1977; 33 (3): 313-319

    Abstract

    Interferon inhibits the early phase of mitogenic action of Concanavalin A on lymphocytes as measured by incorporation of labelled precursors in RNA, DNA or protein. There was no evidence for a role of cyclic AMP in the process of inhibition. Dialysis of interferon against high salt and urea did not separate cell inhibitory activity from antiviral activity. Thus, these results are compatible with the possibility that the antiviral and cell inhibitory activities are in the same molecule. However, further purification of the interferon will be required to verify this assumption.

    View details for Web of Science ID A1977DT73700005

    View details for PubMedID 198357

  • IMMUNOSUPPRESSIVE EFFECT OF TYPE-II MOUSE INTERFERON PREPARATIONS ON ANTIBODY-PRODUCTION CELLULAR IMMUNOLOGY Sonnenfeld, G., MANDEL, A. D., Merigan, T. C. 1977; 34 (2): 193-206

    View details for Web of Science ID A1977EF36300001

    View details for PubMedID 338162

  • INTERFERON-PRODUCTION DURING LYMPHOCYTIC CHORIOMENINGITIS VIRUS-INFECTION OF NUDE AND NORMAL MICE NATURE Merigan, T. C., Oldstone, M. B., Welsh, R. M. 1977; 268 (5615): 67-68

    View details for Web of Science ID A1977DM06700045

    View details for PubMedID 301989

  • CAN IMMUNIZATION ERADICATE VIRAL DISEASES ARCHIVES OF INTERNAL MEDICINE RAND, K. H., Merigan, T. C. 1977; 137 (6): 723-724

    View details for Web of Science ID A1977DH99000002

    View details for PubMedID 869642

  • RECIPROCAL CHANGES IN INTERFERON-PRODUCTION AND IMMUNE-RESPONSES OF MOUSE SPLEEN-CELLS FRACTIONATED OVER COLUMNS OF INSOLUBILIZED CONJUGATES OF HISTAMINE CELLULAR IMMUNOLOGY Brodeur, B. R., Weinstein, Y., Melmon, K. L., Merigan, T. C. 1977; 29 (2): 363-372

    View details for Web of Science ID A1977DB15700015

    View details for PubMedID 324636

  • Cellular immunity to herpes simplex infection in humans. Survey of ophthalmology Rasmussen, L., Haahr, S., Merigan, T. C. 1976; 21 (2): 191-193

    Abstract

    A comparison of lymphocyte interferon production and transformation as in vitro parameters of cellular immunity to herpes simplex in humans in different types of mononuclear cell cultures is reported. Mononuclear cells were purified on Ficoll-Hypaque gradients and nylon fiber columns (purified T lymphocytes). Reactivity was then compared to that observed in autochthonous macrophage-lymphocyte cultures. The quantity and type (I or II) of interferon, as well as the magnitude of the transformation response, is affected by the type of cell culture used for assay. The kinetics of lymphocyte reactivity in doners studied within 12 weeks after disease were compared to those occurring at greater than 12 weeks after disease and in seronegative donors. The observed kinetics were variable according to the methods used to prepare mononuclear cells for culture.

    View details for PubMedID 1086514

  • LYMPHOCYTE-TRANSFORMATION AND INTERFERON-PRODUCTION IN HUMAN MONONUCLEAR CELL MICROCULTURES FOR ASSAY OF CELLULAR IMMUNITY TO HERPES-SIMPLEX VIRUS INFECTION AND IMMUNITY Haahr, S., Rasmussen, L., Merigan, T. C. 1976; 14 (1): 47-54

    Abstract

    Interferon production and transformation in response to herpes simplex virus antigen were studied in microcultures of human mononuclear cells. Mononuclear cells consisting of monocytes and both T and B lymphocytes were purified by Ficoll-Hypaque gradients. Lymphocytes, predominantly T with 5% B, were obtained by passage of buffy-coat cells through nylon fiber columns. For some experiments, autochthonous macrophages and column-purified lymphocytes were stimulated with herpesvirus antigen. The effect of specific antibody and cell concentration on reactivity is described. Crude and purified antigens were compared as cell culture stimulants. Significant differences in transformation and interferon were observed between donors with a history of herpes labialis and donors with no detectable antibody, both in cultures prepared by Ficoll-Hypaque gradients and by column purification of lymphocytes. Cultures from seronegative donors prepared by Ficoll-Hypaque gradients produced interferon but did not transform when stimulated by herpes simplex antigen. "Immune" interferon production, that is, type II as opposed to type I, occurred only with autochthonous macrophage and column-purified lymphocyte cultures. Interferon produced by Ficoll-Hypaque-purified mononuclear cultures was type I, and its production was unrelated to immune status. Similarly, column-purified lymphocytes responded to herpes simplex virus antigen with type I interferon if obtained from a seropositive donor.

    View details for Web of Science ID A1976BZ02500008

    View details for PubMedID 181328

  • NOSOCOMIAL VACCINIA INFECTION WESTERN JOURNAL OF MEDICINE Johnson, R. H., KRUPP, J. R., Hoffman, A. R., Koplan, J. P., NAKANO, J. H., Merigan, T. C. 1976; 125 (4): 266-270

    Abstract

    Although hospital-associated spread of vaccinia has been reported in the past, there have been no recent reports. This paper describes hospital-associated spread of vaccinia virus infection, supplies data on the environmental survival of vaccinia virus and offers recommendations for the management of patients with vaccinia that may minimize the hazard of infection in other high-risk patients.

    View details for Web of Science ID A1976CH55100002

    View details for PubMedID 1032226

  • Progressive multifocal leukoencephalopathy: clinical pathological correlates and failure of a drug trial in two patients. Transactions of the American Neurological Association Wolinsky, J. S., Johnson, K. P., Rand, K., Merigan, T. C. 1976; 101: 81-82

    View details for PubMedID 1028274

  • ROLE OF INTERFERON IN PROPHYLAXIS OF RABIES AFTER EXPOSURE JOURNAL OF INFECTIOUS DISEASES WIKTOR, T. J., Koprowski, H., Mitchell, J. R., Merigan, T. C. 1976; 133: A260-A265

    Abstract

    Rhesus monkeys were completely protected from rabies by a single dose of experimental, highly concentrated, rabies virus vaccine prepared from virus propagated in cultures of human diploid cells and administered several hours after infection with street rabies virus. Protection seemed to be related to the high antigenicity of the vaccine and to its ability to induce interferon in vaccinated animals. Only partial protection was afforded by one or three inoculations of less concentrated vaccines that were prepared from cultures of human diploid cells or primary hamster kidney cells and that were not capable of inducing interferon. The level of virus-neutralizing antibody induced by vaccination could not be correlated with the final outcome of the disease. The simultaneous inoculation of vaccine and interferon inducers (polyribocytidylic acid homopolymer pair or Newcastle disease virus) did not improve the results obtained with vaccine along, a fact which indicates that factors other than interferon and antibody may play an important role in the treatment of rabies after exposure.

    View details for Web of Science ID A1976BY51400046

    View details for PubMedID 819599

  • EFFICACY OF ADENINE ARABINOSIDE IN HERPES-ZOSTER NEW ENGLAND JOURNAL OF MEDICINE Merigan, T. C. 1976; 294 (22): 1233-1234

    View details for Web of Science ID A1976BR85600012

    View details for PubMedID 772429

  • VIRUS-INFECTIONS INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Stevens, D. A., Merigan, T. C. 1976; 1 (3-4): 317-320

    View details for Web of Science ID A1976BL53400022

    View details for PubMedID 184072

  • DIAGNOSIS OF CYTOMEGALOVIRUS PNEUMONIA IN COMPROMISED HOSTS AMERICAN JOURNAL OF MEDICINE ABDALLAH, P. S., Mark, J. B., Merigan, T. C. 1976; 61 (3): 326-332

    Abstract

    Sixteen patients with cytomegalovirus pulmonary infection are described. In 11 the diagnosis was made antemortem by lung aspirate or biopsy, and in five the diagnosis was made at postmortem by typical lung histology and positive viral lung cultures. All patients were immunosuppressed by both their underlying diseases and treatment with corticosteroids and other chemotherapy. Although other pathogens were identified at lung biopsy in most patients (73 per cent), primarily Pneumocystis carinii, evidence is offered to demonstrate that cytomegalovirus can cause significant pulmonary disease alone, leading to respiratory failure and death.

    View details for Web of Science ID A1976CD77200005

    View details for PubMedID 183499

  • EFFECT OF HUMAN LEUKOCYTE INTERFERON ON HEPATITIS B VIRUS-INFECTION IN PATIENTS WITH CHRONIC ACTIVE HEPATITIS NEW ENGLAND JOURNAL OF MEDICINE Greenberg, H. B., Pollard, R. B., Lutwick, L. I., Gregory, P. B., Robinson, W. S., Merigan, T. C. 1976; 295 (10): 517-522

    Abstract

    Four patients with chronic hepatitis B infection and chronic active hepatitis were treated with human leukocyte interferon. Three of them had consistently elevated levels of circulating Dane-particle markers, including Dane-particle-associated DNA polymerase activity, hepatitis B core antigen and Dane-particle-associated DNA. Parenteral interferon administration at a dosage between 6.0 X 10(3) and 17 X 10(4) U per kilogram per day was associated with a rapid and reproducible fall in all Dane-particle markers in the three patients. The suppressive effect was transient when the interferon was given for 10 days or less but appeared to be more permanent when administration was prolonged for a month or more. In addition, long-term interferon therapy was associated with a marked fall in hepatitis B surface antigen in two of three patients and a disappearance of e antigen in two of two patients. Interferon may be useful in limiting carrier infectivity or eradicating chronic infection.

    View details for Web of Science ID A1976CB97100001

    View details for PubMedID 950957

  • EFFECT OF LEUKOCYTE INTERFERON ON URINARY-EXCRETION OF CYTOMEGALOVIRUS BY INFANTS JOURNAL OF INFECTIOUS DISEASES Arvin, A. M., YEAGER, A. S., Merigan, T. C. 1976; 133: A205-A210

    Abstract

    Five infants with symptomatic cytomegalovirus infections and high urinary titers of cytomegalovirus were treated with interferon in doses of 1.7-3.5 X 10(5) reference units/kg per day for seven to 14 days. Six courses of treatment were given. One of two infants treated with the largest dose of interferon had transient suppression of viruria; no suppression was noted during the other five courses of treatment. Adverse effects noted included a low rate of weight gain, a transient elevation of serum aspartate aminotransferase and fever. Further trials are needed to determine whether larger doses of a more purified preparation of interferon will eliminate viruria in infants with sytomegalovirus infection, but careful assessment of toxicity will be necessary in this population of patients.

    View details for Web of Science ID A1976BY51400037

    View details for PubMedID 180201

  • MEASLES IN ADULTS - UNFORESEEN CONSEQUENCE OF IMMUNIZATION JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION RAND, K. H., EMMONS, R. W., Merigan, T. C. 1976; 236 (9): 1028-1031

    Abstract

    An outbreak of measles occurred in California in the first half of 1975, especially in the San Francisco Bay area. Of four adult patients with complicated cases, two were receiving immunosuppressive chemotherapy, and both died from a giant-cell pneumonia. The clinical presentation in such cases may be atypical, and special viral isolation and immunofluorescent techniques may be diagnostically helpful. A significant (P less than .0005) trend toward the occurrence of measles in adolescents was observed in this epidemic, which may also occur in future epidemics elsewhere. With wide spread but incomplete immunization, it is possible for the nonimmunized to reach adulthood without acquiring natural infection. As a result, internists as well as pediatricians will have to consider the possibility of measles and be aware of its serious potential in the immunosuppressed patient.

    View details for Web of Science ID A1976CB98300020

    View details for PubMedID 787566

  • ANTI-VIRALS WITH CLINICAL POTENTIAL - SYMPOSIUM AT STANFORD-UNIVERSITY, STANFORD, CALIFORNIA - AUGUST 26-29, 1975 - INTRODUCTION AND DEDICATION JOURNAL OF INFECTIOUS DISEASES Merigan, T. C. 1976; 133: A1-A2

    View details for Web of Science ID A1976BY51400001

    View details for PubMedID 932499

  • The lact of antiviral effect of (polyinosinic acid): (polycytidylic acid) when attached to insoluble supports. journal of general virology HUTCHINSON, D. W., Merigan, T. C. 1975; 27 (3): 403-407

    Abstract

    A local antiviral effect can be observed when (poly rI)-(poly rC), bound to Visking discs by u.v. irradiation, is incubated with monolayers of human foreskin fibroblast cells. Radioactive labelling of cytosine residues in (poly rI)-(poly rC) with -125I, has provided a much more sensitive method for determining the fate of the insoluble (poly rI)-(poly rC) than has been available hitherto. The antiviral effect is not related to the amount of (poly rI)-(POLY RC) present on the insoluble support but rather to the amount of polynucleotide lost from the support during incubation. Treatment of (poly rI)-(poly rC) which had been bound to cyanogen bromide-activated Sepharose with eigher dilute alkali or pancreatic ribonuclease released virtually all the polynucleotide. A small amount of (poly rI)-(poly rC) is released from the insoluble matrix in the presence of serum-free Minimum Eagle's Medium.

    View details for PubMedID 167121

  • ENHANCEMENT OF HOST DEFENSE-MECHANISMS BY PHARMACOLOGICAL AGENTS ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY Jordan, G. W., Merigan, T. C. 1975; 15: 157-175

    View details for Web of Science ID A1975W083400008

    View details for PubMedID 1096788

  • CELLULAR EVENTS IN ZOSTER VESICLES - RELATION TO CLINICAL COURSE AND IMMUNE PARAMETERS JOURNAL OF INFECTIOUS DISEASES Stevens, D. A., FERRINGTON, R. A., Jordan, G. W., Merigan, T. C. 1975; 131 (5): 509-515

    Abstract

    The cellular responses in zoster vesicles was studied chronologically in 30 patients, some of whom were compromised hosts with disseminated disease. Cell counts were low initially but rose abuptly later. Polymorphonuclear leukocytes predominated at all times in the vesicular fluid and in the cells adherent to the vesicle base. The abrupt rise in the number of cells generally coincided with an abrupt rise in the titer of vesicular interferon; both increases preceded resolution of local infection and cessation of cutaneous dissemination in disseminated disease, but the sequence of the increases was variable. The peak interferon titer correlated with cessation of dissemination better than did peak cell counts, and the timing of the local events contrasted with appearance of complement-fixing antibody, which commonly occurred after the resolution of disease. Possible interpretations are that a few sensitized lymphocytes may initiate the defensive response, produce interferon, and/or produce chemotactic factors that augment the polymorphonuclear response. The appearance of polymorphonuclear cells may be a nonspecific inflammatory response, or these cells or the deeper mononuclear infiltrate seen in biopsies may contribute to the rise in local interferon.

    View details for Web of Science ID A1975AC71900002

    View details for PubMedID 165243

  • CHARACTERISTICS OF IMMUNE INTERFERON PRODUCED BY HUMAN LYMPHOCYTE-CULTURES COMPARED TO OTHER HUMAN INTERFERONS JOURNAL OF IMMUNOLOGY Valle, M. J., Jordan, G. W., Haahr, S., Merigan, T. C. 1975; 115 (1): 230-233

    Abstract

    A factor with antiviral activity has been produced in vitro by combined macrophage-lymphocyte cultures from patients with recent herpes labialis in response to HSV antigen stimulation. It has been designated "immune interferon" and characterized in comparison to several other human interferons. It was shown to be relatively unstable at pH 2 and at 56 degrees C. Rabbit anti-human leukocyte interferon serum was shown to be less active against immune interferon than against diploid cell interferon or against vesicle fluid interferon. The possibility of immune interferon being a totally different anti-viral protein or a protein with certain shared antigen determinants or structures with classical viral interferon is discussed. A simplified method for the assay of anti-interferon sera with microtiter plates is also described.

    View details for Web of Science ID A1975AJ26600043

    View details for PubMedID 239056

  • RANDOMIZED TRIAL OF TRANSFER-FACTOR TREATMENT OF HUMAN WARTS CLINICAL AND EXPERIMENTAL IMMUNOLOGY Stevens, D. A., FERRINGTON, R. A., Merigan, T. C., Marinkovich, V. A. 1975; 21 (3): 520-524

    Abstract

    Dialysed transfer factor, prepared from the leucocytes of a donor whose warts had undergone recent spontaneous regression, was used in the treatment of a child with the Wiskott--Aldrich syndrome. The child then had a spontaneous regression at multiple warty areas. A similar relationship was seen in four otherwise healthy patients in a pilot study. A randomized double-blind study of thirty patients failed to confirm a causal relationship between the transfer factor therapy (equivalent to 2-1 X 10(8) leucocytes) and wart regressions. The need for randomized trials of transfer factor therapy for diseases with a variable natural history is emphasized.

    View details for Web of Science ID A1975AP56500018

    View details for PubMedID 1106927

  • 'Non-specific' mediators in host defense against respiratory viruses: assay methods and results. Developments in biological standardization Merigan, T. C. 1975; 28: 211-223

    Abstract

    Understandably, there is interest in further defining the nature of 'non-specific' defenses. This, in fact, would clarify the specific nature of their appearance and action, as well as their role in host defense. Therefore, 'non-specific' defenses in my discussion will be taken to mean non-immune defenses in virus infections. Tissue or respiratory tract organ cultures are convenient means of studying host defenses in the absence of immune responses. Factors to be controlled in making observations with such systems will be discussed which help 'in vitro' results to parallel 'in vivo' findings. 'In vitro' and 'in vivo' methods and results probing importance of mucous barrier, ciliary activity, temperature and pH will be reviewed. Critical points in separating cellular and humoral immune functions from non-specific mediators will also be touched on. This distinction is complicated by the fact that both limbs of immunity work in close concert with macrophages, PMN's complement and other inflammatory responses. Interferon and macrophage mobilization are examples of 'non-specific' responses which have more recently become complicated by their recognition as part of the effector limb of the cell-mediated immune responses. Finally, methods will also be presented for distinguishing human interferon of the immune-specific variety associated with cell-mediated immunity from that produced by viral infection of non-immune cells.

    View details for PubMedID 1126570

  • MECHANISM OF SUPPRESSIVE EFFECT OF INTERFERON ON ANTIBODY-SYNTHESIS INVIVO JOURNAL OF IMMUNOLOGY Brodeur, B. R., Merigan, T. C. 1975; 114 (4): 1323-1328

    Abstract

    Mouse interferon preparations significantly suppress the in vivo antibody response to sheep red blood cells (SRBC), a thymus-dependent antigen, and to Salmonella typhimurium lipopolysaccharide (LPS), a thymus-independent antigen. It is also possible to effect the late responses of antigen sensitive "memory" cells observed during secondary immunization by administration of interferon prior to primary immunization. The immunosuppressive activity of interferon was time- and dose-dependent. Maximum suppression was produced when animals were given 1.5 times 10-5 units of interferon between 4 and 48 hr before antigenic stimulation. These findings suggested that interferon affects some early event(s) in the process of antibody synthesis which might be related to the general inhibitory effect of interferon on rapidly dividing cells and viral m-RNA translation. In addition, the use of nonadherent spleen cell cultures from interferon-treated mice, immunized in vitro with a thymus-independent antigen, indicated that in this situation the inhibitory effect of interferon was due to an action on B lymphocytes. A variety of soluble "suppressive" factors are secreted by T cells as a consequence of activation by mitogens or specific antigens in vitro. Since T cells are recognized as one of the sources of interferon, it is suggested that interferon should be investigated as a suppressor T cell-produced lymphokine which can regulate B cell expression.

    View details for Web of Science ID A1975W126400034

    View details for PubMedID 163863

  • IMMUNE SPECIFIC PRODUCTION OF INTERFERON BY HUMAN T-CELLS IN COMBINED MACROPHAGE-LYMPHOCYTE CULTURES IN RESPONSE TO HERPES-SIMPLEX ANTIGEN JOURNAL OF IMMUNOLOGY Valle, M. J., Bobrove, A. M., Strober, S., Merigan, T. C. 1975; 114 (1): 435-441

    Abstract

    Human peripheral blood lymphocytes, highly enriched for T cells, were obtained by passing gravity-sedimented leukocytes through nylon wool columns. The eluted cells were cultured with autologous macrophages and the mixture was studied for its capacity to produce interferon in vitro in response to stimulation with herpes simplex virus antigen. The interferon produced by the combined macrophage-lymphocyte cultures was shown to depend upon the presence of T cells; elimination of these cells by treatment with an anti-T cell serum plus complement greatly diminished the amount of interferon produced. The memory for the immune-specific release of interferon also appeared to be carried by the T lymphocytes rather than the glass-adherent macrophages. Furthermore, the results suggest that under our conditions of culture immune-specific interferon originates from T cells.

    View details for Web of Science ID A1975W269900035

    View details for PubMedID 46881

  • Quantitative aspects of interferon-induced plaque reduction: effects of cell age and dose of challenge virus. Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.) Jordan, G. W., Merigan, T. C. 1974; 145 (3): 1037-1041

    View details for PubMedID 4362002

  • INTERFERON-PRODUCTION BY INDIVIDUAL CELLS VIROLOGY Rodgers, R., Merigan, T. C. 1974; 57 (2): 467-474

    View details for Web of Science ID A1974S099700017

    View details for PubMedID 4361456

  • SUPPRESSIVE EFFECT OF INTERFERON ON HUMORAL IMMUNE-RESPONSE TO SHEEP RED BLOOD-CELLS IN MICE JOURNAL OF IMMUNOLOGY Brodeur, B. R., Merigan, T. C. 1974; 113 (4): 1319-1325

    View details for Web of Science ID A1974U262000033

    View details for PubMedID 4607133

  • LYMPHOCYTE INTERFERON-PRODUCTION AND TRANSFORMATION AFTER HERPES-SIMPLEX INFECTIONS IN HUMANS JOURNAL OF IMMUNOLOGY RASMUSSE, L. E., Jordan, G. W., Stevens, D. A., Merigan, T. C. 1974; 112 (2): 728-736

    View details for Web of Science ID A1974S040600036

    View details for PubMedID 4360547

  • INFLUENCE OF INCREASING 2'-O-METHYLATION ON INTERFERON STIMULATING CAPACITY OF POLY(RL) .POLY(RC) VIROLOGY Merigan, T. C., ROTTMAN, F. 1974; 60 (1): 297-301

    View details for Web of Science ID A1974T785500031

    View details for PubMedID 4366498

  • REPLICATION OR INACTIVATION OF DIFFERENT VIRUSES BY HUMAN LYMPHOCYTE PREPARATIONS INFECTION AND IMMUNITY Denman, A. M., RAGERZIS, B., Merigan, T. C., Tyrrell, D. A. 1974; 9 (2): 373-376

    Abstract

    Cultures of phytohemagglutinin-stimulated, unstimulated, and frozen and thawed mononuclear (as controls) cells from normal human donors were infected with different viruses. A variable pattern of virus infectivity was noted, and influenza and Coxsackie virus were rapidly inactivated even by stimulated lymphocytes. Direct inactivation by lymphocytes may be one form of host defense in infection by some viruses.

    View details for Web of Science ID A1974S051800025

    View details for PubMedID 4361296

  • ADMINISTRATION OF HUMAN LEUKOCYTE INTERFERON IN HERPES-ZOSTER .1. SAFETY, CIRCULATING ANTIVIRAL ACTIVITY, AND HOST RESPONSES TO INFECTION JOURNAL OF INFECTIOUS DISEASES Jordan, G. W., FRIED, R. P., Merigan, T. C. 1974; 130 (1): 56-62

    View details for Web of Science ID A1974T583200008

    View details for PubMedID 4601181

  • CELL-MEDIATED-IMMUNITY TO VARICELLA-ZOSTER VIRUS - INVITRO LYMPHOCYTE-RESPONSES JOURNAL OF INFECTIOUS DISEASES Jordan, G. W., Merigan, T. C. 1974; 130 (5): 495-501

    View details for Web of Science ID A1974U701400007

    View details for PubMedID 4370611

  • HOST DEFENSES AGAINST VIRAL DISEASE NEW ENGLAND JOURNAL OF MEDICINE Merigan, T. C. 1974; 290 (6): 323-329

    View details for Web of Science ID A1974R985900008

    View details for PubMedID 4358448

  • INTERFERON - ITS INDUCERS AND SOME ASPECTS OF HOST RESISTANCE IN MALIGNANCY CANCER CHEMOTHERAPY REPORTS PART 1 Merigan, T. C. 1974; 58 (4): 571-578

    View details for Web of Science ID A1974T826200013

    View details for PubMedID 4604626

  • Clinical testing of human interferon in infectious diseases. In vitro. Monograph Merigan, T. C. 1974: 57-62

    View details for PubMedID 4377883

  • An artificial intelligence program to advise physicians regarding antimicrobial therapy. Computers and biomedical research, an international journal Shortliffe, E. H., AXLINE, S. G., Buchanan, B. G., Merigan, T. C., Cohen, S. N. 1973; 6 (6): 544-560

    View details for PubMedID 4589706

  • Inhibition of respiratory virus infection by locally applied interferon. Lancet Merigan, T. C., Reed, S. E., Hall, T. S., TYRRELL, D. A. 1973; 1 (7803): 563-567

    View details for PubMedID 4120640

  • SUPPRESSION OF MOUSE ANTIBODY-PRODUCING SPLEEN-CELLS BY VARIOUS INTERFERON PREPARATIONS NATURE Chester, T. J., PAUCKER, K., Merigan, T. C. 1973; 246 (5428): 92-94

    View details for Web of Science ID A1973R229300029

    View details for PubMedID 4585853

  • ADVERSE EFFECT OF CYTOSINE-ARABINOSIDE ON DISSEMINATED ZOSTER IN A CONTROLLED TRIAL NEW ENGLAND JOURNAL OF MEDICINE Stevens, D. A., Jordan, G. W., WADDELL, T. F., Merigan, T. C. 1973; 289 (17): 873-878

    View details for Web of Science ID A1973R029200001

    View details for PubMedID 4354007

  • STRUCTURE AND INFECTIVITY OF PICORNAVIRAL RNA ENCAPSIDATED BY COWPEA CHLOROTIC MOTTLE VIRUS PROTEIN JOURNAL OF VIROLOGY Black, D. R., Connell, C. J., Merigan, T. C. 1973; 12 (6): 1209-1215

    Abstract

    Poliovirus and Mengo virus RNA were shown to associate efficiently with cowpea chlorotic mottle virus protein to form pseudovirions. The sedimentation coefficient for the pseudovirions was similar to that of poliovirus, and electron microscope observations showed the Mengo pseudovirions to be similar in size to Mengo virus. Such pseudovirions were infectious and were more resistant to ribonuclease than viral RNA; however, under our assay conditions, their infectivity was about equal to that of viral RNA.

    View details for Web of Science ID A1973R192500003

    View details for PubMedID 4128376

  • USEFUL QUANTITATIVE SEMIMICROMETHOD FOR VIRAL PLAQUE ASSAY PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE RAGERZIS, B., Merigan, T. C. 1973; 142 (4): 1174-1179

    View details for Web of Science ID A1973P380600028

    View details for PubMedID 4121080

  • HERPES ZOSTER - RECENT STUDIES NATIONAL CANCER INSTITUTE MONOGRAPHS Stevens, D. A., Merigan, T. C. 1973: 465-468

    View details for Web of Science ID A1973Q863600090

    View details for PubMedID 4744604

  • STUDIES ON TOXICITY AND ANTIVIRAL ACTIVITY OF VARIOUS POLYNUCLEOTIDES ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Black, D. R., Eckstein, F., DECLERCQ, E., Merigan, T. C. 1973; 3 (2): 198-206

    Abstract

    Various polynucleotides were examined for antiviral activity and toxicity in mice. Although the antiviral potency of the various interferon inducers varied, there was a concomitant variation in toxicity. This was reflected by a fivefold range in therapeutic ratio for the various compounds. In addition, no polynucleotide proved to be a more potent interferon inducer than polyinosinic.polycytidylic acid [(poly rI).(poly rC)]. Our results suggest that there may be intrinsic limitations to the development of polynucleotide interferon inducers having improved therapeutic ratios.

    View details for Web of Science ID A1973O939100011

    View details for PubMedID 4790587

  • EFFECT OF BURSECTOMY AND THYMECTOMY ON COURSE OF AVIAN INFLUENZA-VIRUS INFECTION CELLULAR IMMUNOLOGY Portnoy, J., Bloom, K., Merigan, T. C. 1973; 9 (2): 251-262

    View details for Web of Science ID A1973R168900008

    View details for PubMedID 4752847

  • Cat interferon inhibits feline leukaemia virus infection in cell culture. Nature: New biology Rogers, R., Merigan, T. C., Hardy, W. D., Old, L. J., Kassel, R. 1972; 237 (78): 270-271

    View details for PubMedID 4504461

  • Interferon and its inducers: antiviral and other effects. CRC critical reviews in clinical laboratory sciences Rodgers, R., Merigan, T. C. 1972; 3 (2): 131-162

    View details for PubMedID 4559172

  • The antiviral activity of certain thiophosphate and 2'-chloro substituted polynucleotide homopolymer duplexes. Virology Black, D. R., Eckstein, F., Hobbs, J. B., Sternbach, H., Merigan, T. C. 1972; 48 (2): 537-545

    View details for PubMedID 4337034

  • UNCERTAIN ROLE OF CYTOSINE-ARABINOSIDE IN VARICELLA INFECTION OF COMPROMISED HOSTS JOURNAL OF PEDIATRICS Stevens, D. A., Merigan, T. C. 1972; 81 (3): 562-?

    View details for Web of Science ID A1972N285000024

    View details for PubMedID 4340436

  • INTERFERON, ANTIBODY, AND OTHER HOST FACTORS IN HERPES ZOSTER JOURNAL OF CLINICAL INVESTIGATION Stevens, D. A., Merigan, T. C. 1972; 51 (5): 1170-?

    Abstract

    The influence of several factors on the course of herpes zoster was studied in 151 patients. Dissemination of zoster was associated with the presence of a concurrent disease, especially Hodgkin's disease, and/or the use of immunosuppressive therapy. Several host-immune parameters, including quantitative immunoglobulins, circulating lymphocyte counts, delayed hypersensitivity to multiple skin test antigens, and lymphocyte transformation to phytohemagglutinin did not correlate with dissemination of disease. Development of virus-specific complement-fixing antibody (CFA) was delayed in some patients with disseminated disease. Vesicle interferon (V-IF) titers were low early in the disease in patients with localized and disseminated zoster and then rose, usually abruptly, to a peak value and declined as pustulation and crusting occurred. However, titers in patients with localized disease rose at an earlier time. This could be seen in terms of time to development of intermediate values of V-IF or by the day on which the sharpest rise occurred. In 15 carefully studied patients with disseminated disease, the development of the maximum V-IF response was followed within 48 hr by cessation of dissemination. Half of the patients in this group had no CFA detectable until after dissemination had ceased. These findings suggest at least two host factors whose interaction might determine host response to zoster; local interferon production (possibly mediated by sensitized lymphocytes) and humoral antibody, acting to prevent or shorten dissemination of an initially local disease.

    View details for Web of Science ID A1972M302100016

    View details for PubMedID 5020430

  • [Evaluation of teleroentgenography in the surgical and orthodontical treatment of prognathism]. Fogorvosi szemle Black, D. R., Eckstein, F., Hobbs, J. B., Sternbach, H., Merigan, T. C. 1972; 65 (5): 138-144

    View details for PubMedID 4502683

  • STUDIES ON ANTIVIRAL ACTIVITY AND CELL INTERACTION OF SYNTHETIC DOUBLE-STRANDED POLYRIBONUCLEOTIDES AND POLYDEOXYRIBONUCLEOTIDES VIROLOGY DECLERCQ, E., Wells, R. D., Merigan, T. C. 1972; 47 (2): 405-?

    View details for Web of Science ID A1972L562700016

    View details for PubMedID 4333736

  • HERPES ZOSTER-VARICELLA INFECTIONS AND LYMPHOMA ANNALS OF INTERNAL MEDICINE Goffinet, D. R., GLATSTEI, E. J., Merigan, T. C. 1972; 76 (2): 235-?

    View details for Web of Science ID A1972L668900008

    View details for PubMedID 4333227

  • SELECTIVE INCREASE IN LYMPHOCYTE INTERFERON RESPONSE TO VACCINIA ANTIGEN AFTER REVACCINATION PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Epstein, L. B., Stevens, D. A., Merigan, T. C. 1972; 69 (9): 2632-?

    Abstract

    Viral antigen prepared by heat inactivation of vaccinia virus stimulated production of interferon in association with transformation of sensitized human lymphocytes in vitro. Involvement of a macrophage-lymphocyte interaction in production of interferon stimulated by viral antigen was found in which macrophage greatly augmented the amount of interferon produced by lymphocytes. Reimmunization with live vaccinia virus resulted in a selective increase in the ability of lymphocytes to produce interferon in the presence of viral antigen 4-7 weeks later without a corresponding increase in the degree of already significant lymphocyte transformation. There was no correlation between the extent of lymphocyte transformation and the amount of interferon produced. The augmented interferon response after reimmunization described in this study may be a significant component of the protective effect of immunization with vaccinia against disease occurring after exposure to small-pox.

    View details for Web of Science ID A1972N512500065

    View details for PubMedID 4506785

  • IN-VIVO RELEASE OF PREVIOUSLY CLEARED INTERFERON BY CYCLOHEXIMIDE INFECTION AND IMMUNITY Chester, T. J., DECLERCQ, E., Nuwer, M. R., Merigan, T. C. 1972; 5 (3): 383-?

    Abstract

    The release of previously cleared interferon by cycloheximide was studied in the mouse. When cycloheximide was administered after either endogenous interferon stimulation or administration of exogenous interferon, the clearance of interferon from the blood stream was interrupted and a sharp rise in interferon titer occurred approximately 6 hr after cycloheximide administration followed by a rapid decline to low levels. This effect was observed with either interferon stimulated endogenously (by polyriboinosinic.polyribocytidylic acid), or homologous (mouse) or heterologous (rabbit) interferon administered exogenously. Serum protein concentrations also exhibited this rise and fall phenomenon after cycloheximide administration although the magnitude of the change in protein concentrations was less pronounced than that observed with interferon. Hematocrits, although elevated in mice receiving cycloheximide, did not exhibit this rise and fall phenomenon. Hence, cycloheximide administration leads to the release into the circulation of previously cleared interferon as well as other proteins.

    View details for Web of Science ID A1972L859300018

    View details for PubMedID 4636292

  • Approaches to the control of viral infections in man. Rational drug therapy Stevens, D. A., Merigan, T. C. 1971; 5 (9): 1-5

    View details for PubMedID 5105931

  • Interferon clearance rate decreased after repeated injections. journal of general virology Nuwer, M. R., De Clercq, E., Merigan, T. C. 1971; 12 (2): 191-194

    View details for PubMedID 4330791

  • Varicella zoster virus: interferon production and comparative interferon sensitivity in human cell cultures. journal of general virology Armstrong, R. W., Merigan, T. C. 1971; 12 (1): 53-54

    View details for PubMedID 4329449

  • INTERACTION OF HUMAN MACROPHAGES AND LYMPHOCYTES IN PHYTOHEMAGGLUTININ-STIMULATED PRODUCTION OF INTERFERON JOURNAL OF CLINICAL INVESTIGATION Epstein, L. B., Cline, M. J., Merigan, T. C. 1971; 50 (4): 744-?

    Abstract

    In studies of 13 normal adults to determine the blood cell types responsible for interferon production induced by phytohemagglutinin, the following observations were made. (a) In cultures containing 96-100% pure macrophages derived from blood monocytes, no interferon was detected in either the presence or the absence of phytohemagglutinin for up to 92 hr. (b) In cultures of 99.5-100% pure lymphocytes, low levels of interferon were detected in the presence, but not in the absence, of phytohemagglutinin. (c) An average fivefold increase in interferon titers occurred when pure lymphocytes were combined with the macrophages in culture with phytohemagglutinin. The peak response of interferon occurred at 68 hr after the initiation of the combined cultures. For maximum response, phytohemagglutinin was required for the duration of the culture, and both cell types in association were necessary. Medium from phytohemagglutinin-stimulated macrophages or lymphocytes could not substitute for the corresponding intact cell. However, frozen-thawed macrophages in combination with lymphocytes and phytohemagglutinin produced an intermediate interferon response. An increase in either cell type produced an increased response in the range studied: lymphocytes, 0.45-1.8 x 10(6) per ml; and macrophages, 0.5-2.1 x 10(5) per ml. Syngeneic fibroblasts, HeLa cells, or mouse macrophages could not substitute for the human macrophages in the combined cultures with phytohemagglutinin. (d) Although all cultures producing interferon showed some degree of transformation (thymidine-(3)H incorporation into deoxyribonucleic acid), no direct correlation between the degree of phytohemagglutinin-induced lymphocyte transformation and the interferon titers was observed.The demonstration of macrophage-lymphocyte interaction in the production of interferon is of interest in view of the known interrelationship of these same cell types in antibody synthesis and cellular immunity.

    View details for Web of Science ID A1971I920400003

    View details for PubMedID 16695958

  • INHIBITION OF RUBELLA VIRUS-SPECIFIC RNA SYNTHESIS BY INTERFERON PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE Wong, K. T., Robinson, W. S., Merigan, T. C. 1971; 136 (2): 615-?

    View details for Web of Science ID A1971I583300066

    View details for PubMedID 5544507

  • APPROACH TO DIAGNOSIS AND TREATMENT OF HERPES SIMPLEX ENCEPHALITIS - REPORT OF 2 CASES CALIFORNIA MEDICINE Gurwith, M. J., Harman, C. E., Merigan, T. C. 1971; 115 (6): 63-?

    View details for Web of Science ID A1971L217900023

    View details for PubMedID 4332110

  • PPD-STIMULATED INTERFERON - IN-VITRO MACROPHAGE-LYMPHOCYTE INTERACTION IN PRODUCTION OF A MEDIATOR OF CELLULAR IMMUNITY CELLULAR IMMUNOLOGY Epstein, L. B., Cline, M. J., Merigan, T. C. 1971; 2 (6): 602-?

    View details for Web of Science ID A1971L246300008

    View details for PubMedID 4360795

  • BIS-DEAE-FLUORENONE - MECHANISM OF ANTIVIRAL PROTECTION AND STIMULATION OF INTERFERON PRODUCTION IN MOUSE JOURNAL OF INFECTIOUS DISEASES DECLERCQ, E., Merigan, T. C. 1971; 123 (2): 190-?

    View details for Web of Science ID A1971I512700008

    View details for PubMedID 5544144

  • THERMAL ACTIVATION OF ANTIVIRAL ACTIVITY OF SYNTHETIC DOUBLE-STRANDED POLYRIBONUCLEOTIDES JOURNAL OF MOLECULAR BIOLOGY DECLERCQ, E., Wells, R. D., Grant, R. C., Merigan, T. C. 1971; 56 (1): 83-?

    View details for Web of Science ID A1971I727400007

    View details for PubMedID 4324809

  • EFFECT OF SEPARATE AND COMBINED INJECTIONS OF POLY RI-POLY RC AND ENDOTOXIN ON RETICULOENDOTHELIAL ACTIVITY, INTERFERON, AND ANTIBODY PRODUCTION IN MOUSE INFECTION AND IMMUNITY Chester, T. J., DECLERCQ, E., Merigan, T. C. 1971; 3 (4): 516-?

    Abstract

    The effect of repeated stimulation on both the interferon and antibody systems and on reticuloendothelial activity was studied by injection of endotoxin 2 days before injection of (poly rI):(poly rC). A single injection of endotoxin or (poly rI):(poly rC) increased or decreased the response in each system depending on the time of administration. If the injection of (poly rI):(poly rC) was preceded by an injection of endotoxin 2 days before, its activity was markedly reduced in all of the three systems studied. Although different doses of endotoxin were required to induce a state of hyporeactivity or tolerance to the effects of (poly rI):(poly rC) in either system, it is possible that a common mechanism underlies the hyporeactivity in all systems.

    View details for Web of Science ID A1971J166600003

    View details for PubMedID 16558008

  • SEPTICEMIA WITH PASTEURELLA-PSEUDOTUBERCULOSIS AND LIVER DISEASE ARCHIVES OF INTERNAL MEDICINE Marlon, A., Gentry, L., Merigan, T. C. 1971; 127 (5): 947-?

    View details for Web of Science ID A1971J354500019

    View details for PubMedID 5560870

  • VIRAL INFECTIONS IN MAN ASSOCIATED WITH ACQUIRED IMMUNOLOGICAL DEFICIENCY STATES FEDERATION PROCEEDINGS Merigan, T. C., Stevens, D. A. 1971; 30 (6): 1858-?

    View details for Web of Science ID A1971K972200024

    View details for PubMedID 4333313

  • INHIBITION OF RADIOGENIC LYMPHOMA DEVELOPMENT IN MICE BY INTERFERON PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE LIEBERMA, M., Merigan, T. C., KAPLAN, H. S. 1971; 138 (2): 575-?

    View details for Web of Science ID A1971K947700042

    View details for PubMedID 5171161

  • HEMOLYTIC-UREMIC-LIKE SYNDROME FOLLOWING POLYCARBOXYLATE INTERFERON INDUCTION - TREATMENT OF DAWSONS INCLUSION-BODY ENCEPHALITIS AMERICAN JOURNAL OF DISEASES OF CHILDREN LEAVITT, T. J., Merigan, T. C., Freeman, J. M. 1971; 121 (1): 43-?

    View details for Web of Science ID A1971I199900011

    View details for PubMedID 5539813

  • EFFECT OF INTERFERON AND INTERFERON INDUCERS ON AVIAN INFLUENZA JOURNAL OF INFECTIOUS DISEASES Portnoy, J., Merigan, T. C. 1971; 124 (6): 545-?

    View details for Web of Science ID A1971L034600003

    View details for PubMedID 5166655

  • Effect of interferon on the replication of Sendai virus. journal of general virology Richman, D. D., Wong, K. T., Robinson, W. S., Merigan, T. C. 1970; 9 (2): 141-150

    View details for PubMedID 4320690

  • The antiviral activity of thiophosphate-substituted polyribonucleotides in vitro and in vivo. Virology CDe Clercq, E., Eckstein, F., Sternbach, H., Merigan, T. C. 1970; 42 (2): 421-428

    View details for PubMedID 4321302

  • Nonviral interferon inducers. journal of general physiology Merigan, T. C., De Clercq, E., BAUSEK, G. H. 1970; 56 (1): 57-75

    Abstract

    Interferon production can be stimulated by a great variety of microbial and nonmicrobial agents other than viruses. The nonmicrobial inducers can be divided into polyanions, mitogens, and a miscellaneous category including the various endotoxins and antibiotics. The polyanions appear to require a stable, high molecular weight backbone and a high density of free anionic groups whether they are polynucleotides, plastics, or polysaccharides. Mitogen-induced interferon appears to be but one of a constellation of substances produced following lymphocyte transformation. The process of transformation can be stimulated either by specific immune recognition or non-specifically by phytohemagglutinin. Synthetic polynucleotide inducers are active; the thermostable, double-stranded RNA's are much more active than the double-stranded DNA's or 1-, 3-, or 4-stranded RNA's. Some success has been obtained with potentiation of nucleotide inducers through the use of polycationic substances, complexing with a polysaccharide, concurrent administration of a metabolic antagonist, or substitution of phosphate by thiophosphate in the polynucleotide backbone. The stages in the interaction of interferon stimulating RNA and cells can be divided into three steps: first, binding to cell surface, next, a temperature dependent "recognition" step, and finally, degradation and utilization of monomers in cellular RNA synthesis; the critical recognition site has not yet been determined. The vast majority of cell-associated polynucleotide remains at the surface of the cell. Information from animal models resembling human diseases suggests that certain of these nucleotide inducers may have clinical usefulness in therapy or prophylaxis.

    View details for PubMedID 19873675

  • Potentiating Effect of Freund's Adjuvant on Interferon Production by Endotoxin or Poly rI*Poly rC. Infection and immunity De Clercq, E., Nuwer, M. R., Merigan, T. C. 1970; 2 (1): 69-76

    Abstract

    Intraperitoneal injection of mice with mineral oil, incomplete (IFA) or complete Freund's adjuvant (CFA) increased the interferon response to endotoxin or (poly rI)*(poly rC) administered intravenously 2 days later. After endotoxin administration, circulating interferon titers were increased at several different times of sampling and with a variety of endotoxin dosages. When injection of endotoxin was delayed until 6 to 8 days after the administration of IFA or CFA, interferon production was markedly decreased. Mice treated with CFA and injected with endotoxin 2 days later became more resistant to intranasal vesicular stomatitis virus challenge than mice injected with endotoxin alone. Hyporeactivity to the interferon-inducing capacity of a second injection of endotoxin 2 days after the first injection could not be overcome by administering CFA simultaneously with the first dose. CFA treatment not only raised the serum interferon titers produced by endotoxin, but also increased the number of interferon-forming cells in the spleen after administration of endotoxin in vivo. In addition, CFA enhanced the intravascular clearance of (poly rI)*(poly rC). The possibility that Freund's adjuvant increased the interferon response to endotoxin and (poly rI)*(poly rC) by stimulating the uptake and processing of the interferon inducer by lymphoreticular cells is discussed.

    View details for PubMedID 16557802

  • SIMULTANEOUS VIRAL AND NON-VIRAL INTERFERON PRODUCTION IN HUMAN CELL CULTURES PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE BAUSEK, G. H., Merigan, T. C. 1970; 133 (3): 982-?

    View details for Web of Science ID A1970F813600056

    View details for PubMedID 5435593

  • ON-LINE COMPUTER QUALITY CONTROL OF ANTIBIOTIC-SENSITIVITY TESTING NEW ENGLAND JOURNAL OF MEDICINE PETRALLI, J., RUSSELL, E., Kataoka, A., Merigan, T. C. 1970; 283 (14): 735-?

    View details for Web of Science ID A1970H419200005

    View details for PubMedID 5201583

  • INTERFERON STIMULATED BY DOUBLE STRANDED RNA NATURE Merigan, T. C. 1970; 228 (5268): 219-?

    View details for Web of Science ID A1970H505000024

    View details for PubMedID 5479520

  • ROLE OF INTERFERON IN PROTECTIVE EFFECT OF A SYNTHETIC DOUBLE-STRANDED POLYRIBONUCLEOTIDE AGAINST INTRANASAL VESICULAR STOMATITIS VIRUS CHALLENGE IN MICE JOURNAL OF CLINICAL INVESTIGATION DECLERCQ, E., Nuwer, M. R., Merigan, T. C. 1970; 49 (8): 1565-?

    Abstract

    Intravenous injection of polyinosinic acid/polycytidylic acid [(poly rI).(poly rC)] offered significant protection against intranasal challenge of young mice with vesicular stomatitis virus (VSV). Optimal protection was obtained when a single dose was administered 2 hr before virus challenge, but repeated doses were effective when started as late as 3 days after virus challenge. The therapeutic ratio or ratio of maximum tolerated dose to minimum effective dose for a single intravenous injection of (poly rI).(poly rC) 2 hr before virus inoculation was >/=8 mg/kg:0.004 mg/kg or >/=200.Dose-response curves for interferon production and antiviral protection by (poly rI).(poly rC) were closely parallel. Equivalent doses of poly rI or poly rC alone did not exert any interferon-inducing capacity or protective effect on intranasal VSV challenge. Several factors, which are known to potentiate or antagonize interferon production, increased or decreased the interferon-inducing capacity and antiviral protection of either (poly rI).(poly rC) or maleic acid/divinyl ether copolymer (MA/DVE) in parallel. Interferon production and antiviral protection by MA/DVE were enhanced by arginine but abolished by prior treatment with MA/DVE; DEAE-dextran (intraperitoneally), kinetin riboside and isopentenyladenosine, and prior injection of endotoxin reduced both interferon production and antiviral protection by (poly rI).(poly rC). Treatment with exogenous interferon in amounts which closely mimicked the levels of circulating interferon produced endogenously by an effective dose of (poly rI).(poly rC) gave protection against intranasal VSV which was identical with that dose of (poly rI).(poly rC). This strongly suggests that interferon production accounts for the whole protective effect of (poly rI).(poly rC) in the intranasal VSV assay.

    View details for Web of Science ID A1970G947700013

    View details for PubMedID 4317283

  • CUTANEOUS INTERFERON PRODUCTION IN PATIENTS WITH HODGKINS DISEASE AND OTHER CANCERS INFECTED WITH VARICELLA OR VACCINIA NEW ENGLAND JOURNAL OF MEDICINE ARMSTRON, R. W., Gurwith, M. J., Waddell, D., Merigan, T. C. 1970; 283 (22): 1182-?

    View details for Web of Science ID A1970H837100002

    View details for PubMedID 4319626

  • 2 MECHANISMS OF CELL RESISTANCE TO REPEATED STIMULATION OF INTERFERON PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE BAUSEK, G. H., Merigan, T. C. 1970; 134 (3): 672-?

    View details for Web of Science ID A1970G853400020

    View details for PubMedID 4317258

  • SYNTHETIC POLYANIONS PROTECT MICE AGAINST INTRACELLULAR BACTERIAL INFECTION NATURE REMINGTO, J. S., Merigan, T. C. 1970; 226 (5243): 361-?

    View details for Web of Science ID A1970G021700055

    View details for PubMedID 5439736

  • SYMPOSIUM ON INTERFERON AND HOST RESPONSE TO VIRUS INFECTION - INTRODUCTION ARCHIVES OF INTERNAL MEDICINE Merigan, T. C. 1970; 126 (1): 49-?

    View details for Web of Science ID A1970G794600001

    View details for PubMedID 5425516

  • FAILURE OF AN INTERFERON INDUCER TO INHIBIT MULTIPLICATION OF MYCOBACTERIUM-LEPRAE PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE Levy, L., Merigan, T. C. 1970; 134 (1): 87-?

    View details for Web of Science ID A1970G364100021

    View details for PubMedID 4912559

  • NONVIRAL INTERFERON INDUCERS JOURNAL OF GENERAL PHYSIOLOGY Merigan, T. C., DECLERCQ, E., BAUSEK, G. H. 1970; 56 (1): S57-?
  • INDUCTION OF INTERFERON BY NONVIRAL AGENTS ARCHIVES OF INTERNAL MEDICINE DECLERCQ, E., Merigan, T. C. 1970; 126 (1): 94-?

    View details for Web of Science ID A1970G794600007

    View details for PubMedID 5425520

  • CURRENT CONCEPTS OF INTERFERON AND INTERFERON INDUCTION ANNUAL REVIEW OF MEDICINE DECLERCQ, E., Merigan, T. C. 1970; 21: 17-?

    View details for Web of Science ID A1970G148900002

    View details for PubMedID 4912475

  • STIMULATION OR INHIBITION OF INTERFRON PRODUCTION DEPENDING ON TIME OF CYCLOHEXIMIDE ADMINISTRATION VIROLOGY DECLERCQ, E., Merigan, T. C. 1970; 42 (3): 799-?

    View details for Web of Science ID A1970H801800027

    View details for PubMedID 4320670

  • INCREASE IN ANTIVIRAL ACTIVITY OF POLYNUCLEOTIDES BY THERMAL ACTIVATION NATURE DECLERCQ, E., Wells, R. D., Merigan, T. C. 1970; 226 (5243): 364-?

    View details for Web of Science ID A1970G021700057

    View details for PubMedID 4314782

  • RESISTANCE TO VIRUS CHALLENGE IN MICE INFECTED WITH PROTOZOA OR BACTERIA PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE REMINGTO, J. S., Merigan, T. C. 1969; 131 (4): 1184-?

    View details for Web of Science ID A1969E249000023

    View details for PubMedID 4309474

  • SUCCESSFUL RENAL ALLOGRAFT IN A PATIENT WITH PULMONARY CRYPTOCOCCUS ARCHIVES OF INTERNAL MEDICINE Swenson, R. S., KOUNTZ, S. L., Blank, N., Merigan, T. C. 1969; 124 (4): 502-?

    View details for Web of Science ID A1969E331500026

    View details for PubMedID 4898545

  • INTERFERON INDUCTION INCREASED THROUGH CHEMICAL MODIFICATION OF A SYNTHETIC POLYRIBONUCLEOTIDE SCIENCE DECLERCQ, E., Eckstein, F., Merigan, T. C. 1969; 165 (3898): 1137-?

    Abstract

    The alternating copolymer riboadenylic-ribouridylic acid gained asignificant increase in ability to stimulate interferon production (2-to 20-fold) and cellular resistance (100-to 10,000-fold) both in vitro and in vivo upon substitution of phosphate by thiophosphate groups. The resulting nucleotide analog was also 10 to 100 times less sensitive to degradation by pancreatic ribonuclease, as determined byresidual antiviral activity.

    View details for Web of Science ID A1969E112900021

    View details for PubMedID 5801596

  • CELL INTERACTION WITH A SYNTHETIC POLYNUCLEOTIDE AND INTERFERON PRODUCTION IN VITRO VIROLOGY BAUSEK, G. H., Merigan, T. C. 1969; 39 (3): 491-?

    View details for Web of Science ID A1969E729400014

    View details for PubMedID 4311546

  • SYNTHESIS OF VIRAL-SPECIFIC RIBONUCLEIC ACID IN RUBELLA VIRUS-INFECTED CELLS JOURNAL OF VIROLOGY Wong, K. T., Robinson, W. S., Merigan, T. C. 1969; 4 (6): 901-?

    Abstract

    Monolayers of BHK-21/W1-2 cells were pulsed with (3)H-uridine at different times after infection with rubella virus, and viral-specific cytoplasmic ribonucleic acid species were demonstrated.

    View details for Web of Science ID A1969E851000014

    View details for PubMedID 16789124

  • EFFECT OF INTERFERON ON COURSE OF SPONTANEOUS AND RADIATION-INDUCED RENAL LESIONS IN RF/UN MOUSE VOX SANGUINIS GUTTMAN, P. H., Davis, W. C., FUDENBER, H. H., Merigan, T. C. 1969; 17 (4): 279-?

    View details for Web of Science ID A1969E402000003

    View details for PubMedID 5262182

  • REQUIREMENT OF A STABLE SECONDARY STRUCTURE FOR ANTIVIRAL ACTIVITY OF POLYNUCLEOTIDES NATURE DECLERCQ, E., Merigan, T. C. 1969; 222 (5199): 1148-?

    View details for Web of Science ID A1969D473800026

    View details for PubMedID 4307027

  • MANAGEMENT OF INFECTED CARDIAC VALVE PROSTHESES JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Walker, S. R., Shumway, N. E., Merigan, T. C. 1969; 208 (3): 531-?

    View details for Web of Science ID A1969D123600016

    View details for PubMedID 5818535

  • AN ACTIVE INTERFERON INDUCER OBTAINED FROM HEMOPHILUS INFLUENZAE TYPE B JOURNAL OF IMMUNOLOGY DECLERCQ, E., Merigan, T. C. 1969; 103 (5): 899-?

    View details for Web of Science ID A1969E632900003

    View details for PubMedID 5307674

  • Interferon induction by and ribonuclease sensitivity of thiophosphate-substituted polyribonucleotides. Antimicrobial agents and chemotherapy De Clercq, E., Eckstein, F., Sternbach, H., Merigan, T. C. 1969; 9: 187-191

    View details for PubMedID 4319308

  • Interferon inducers in vitro: difference in sensitivity to inhbitiros of RNA and protein synthesis. Science Finkelstein, M. S., BAUSEK, G. H., Merigan, T. C. 1968; 161 (3840): 465-468

    Abstract

    Interferon can be induced by diverse agents in a variety of mammalian cell cultures through apparently two mechanisms. One results in an early (2 to 10 hours) appearance of interferon and is relatively resistant to inhibition by actinomycin, puromycin, or fluorophenylalanine. A second mechanism results in a late (18 to 24 hours) appearance of interferon and is more sensitive to inhibition by these inhibitors. The molecular basis for each mechanism is unclear. Since each interferon inducer may have multiple effects on the cell, the differences observed may not necessarily reflect a fundamental difference in the mechanism of interferon stimulation.

    View details for PubMedID 5659681

  • Molecular species of circulating interferon in mice injected with Newcastle disease virus. Virology HALLUM, J. V., YOUNGNER, J. S., Merigan, T. C. 1968; 34 (4): 802-804

    View details for PubMedID 5655724

  • INTERFERON INDUCERS IN VITRO - DIFFERENCE IN SENSITIVITY TO INHIBITORS OF RNA AND PROTEIN SYNTHESIS SCIENCE BAUSEK, G. H., Merigan, T. C. 1968; 161 (3840): 465-?
  • INTERFERON-1968 - HOW MUCH DO WE UNDERSTAND CALIFORNIA MEDICINE FINKELST, M. S., Merigan, T. C. 1968; 109 (1): 24-?

    View details for Web of Science ID A1968B480700006

    View details for PubMedID 4874079

  • MODIFIED SKIN LESIONS DURING CONCURRENT VARICELLA AND MEASLES INFECTIONS JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Merigan, T. C., Waddell, D., Grossman, M., RITCHIE, J. H., Mo, G. 1968; 204 (4): 333-?

    View details for Web of Science ID A1968A986900013

    View details for PubMedID 5694633

  • INTERFERON PRODUCTION IN HUMAN MUMPS INFECTIONS PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE WADDELL, D. J., Wilbur, J. R., Merigan, T. C. 1968; 127 (1): 320-?

    View details for Web of Science ID A1968A787600075

    View details for PubMedID 5644658

  • INTERFERON - PROTECTION OF CELLS INFECTED WITH AN INTRACELLULAR PROTOZOAN (TOXOPLASMA GONDII) SCIENCE REMINGTO, J. S., Merigan, T. C. 1968; 161 (3843): 804-?

    Abstract

    Chick and mouse cell monolayers treated with interferon were significantly protected from destruction by toxoplasma. The results suggest that fewer numbers of organisms were released from interferon-treated cells. Interferons were uniformly more active in a viral assay than in a toxoplasma assay, and they had the same properties in both assays. The data suggest that interferon activity may be directed against organisms phylogenetically higher than viruses.

    View details for Web of Science ID A1968B648400030

    View details for PubMedID 4298747

  • INTERFERON-STIMULATING AND IN VIVO ANTIVIRAL EFFECTS OF VARIOUS SYNTHETIC ANIONIC POLYMERS VIROLOGY Merigan, T. C., FINKELST, M. S. 1968; 35 (3): 363-?

    View details for Web of Science ID A1968B538900004

    View details for PubMedID 4298648

  • Effect of interferon on TRIC agents and induction of interferon by TRIC agents. American journal of ophthalmology Hanna, L., Merigan, T. C., JAWETZ, E. 1967; 63 (5): 1115-1119

    View details for PubMedID 6025157

  • INTERFERONS PROMISE IN CLINICAL MEDICINE - FACT OR FANCY AMERICAN JOURNAL OF MEDICINE Merigan, T. C. 1967; 43 (6): 817-?

    View details for Web of Science ID A1967A372100001

    View details for PubMedID 4862760

  • INTERFERON AND CYTOMEGALOVIRUS IN VIVO AND IN VITRO PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE Glasgow, L. A., HANSHAW, J. B., Merigan, T. C., PETRALLI, J. K. 1967; 125 (3): 843-?

    View details for Web of Science ID A19679701600047

    View details for PubMedID 15938281

  • INDUCTION OF CIRCULATING INTERFERON BY SYNTHETIC ANIONIC POLYMERS OF KNOWN COMPOSITION NATURE Merigan, T. C. 1967; 214 (5086): 416-?

    View details for Web of Science ID A19679232500057

    View details for PubMedID 6032855

  • DEQUOIOSIS - A GRANULOMATOUS PNEUMONITIS ASSOCIATED WITH REDWOOD SAWDUST INHALATION AMERICAN JOURNAL OF MEDICINE Cohen, H. I., Merigan, T. C., Kosek, J. C., ELDRIDGE, F. 1967; 43 (5): 785-?

    View details for Web of Science ID A1967A186900018

    View details for PubMedID 6054842

  • ACTION OF ISOPROTERENOL ON HEART CELLS IN TISSUE CULTURE PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE HARRISON, D. C., Kleiger, R. E., Merigan, T. C. 1967; 124 (1): 122-?

    View details for Web of Science ID A19678813200029

    View details for PubMedID 5334871

  • VARIOUS MOLECULAR SPECIES OF INTERFERON INDUCED BY VIRAL AND NONVIRAL AGENTS BACTERIOLOGICAL REVIEWS Merigan, T. C. 1967; 31 (2): 138-?

    View details for Web of Science ID A19679571000005

    View details for PubMedID 16350204

  • INTERFERONS OF MICE AND MEN NEW ENGLAND JOURNAL OF MEDICINE Feingold, D. S., Parris, E. E., Merigan, T. C. 1967; 276 (16): 913-?

    View details for Web of Science ID A19679190600008

    View details for PubMedID 5336072

  • INTERFERON INDUCTION IN MAN BY A SYNTHETIC POLYANION OF DEFINED COMPOSITION NEW ENGLAND JOURNAL OF MEDICINE Merigan, T. C., REGELSON, W. 1967; 277 (24): 1283-?

    View details for Web of Science ID A1967A300700003

    View details for PubMedID 6073272

  • A second molecular species of mouse interferon in mice injected with statolon. Nature Merigan, T. C., KLEINSCHMIDT, W. J. 1966; 212 (5068): 1383-1384

    View details for PubMedID 5970041

  • Variation in adrenal cortical hormones within physiologic ranges, stress and interferon production in mice. Rivista di patologia nervosa e mentale Solomon, G. F., Merigan, T. C., LEVINE, S. 1966; 87 (4): 74-79

    View details for PubMedID 4294391

  • HETEROGENEITY OF RABBIT SERUM INTERFERONS NATURE Ke, Y. H., Ho, M., Merigan, T. C. 1966; 211 (5048): 541-?

    View details for Web of Science ID A19668028600081

    View details for PubMedID 5338578

  • EFFECT OF CRUDE AND PURIFIED INTERFERONS ON GROWTH OF UNINFECTED CELLS IN CULTURE PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE Baron, S., Merigan, T. C., MCKERLIE, M. L. 1966; 121 (1): 50-?

    View details for Web of Science ID A19667282500015

    View details for PubMedID 4285508

  • HEREDITARY OCCURRENCE OF CYSTIC DISEASE OF RENAL MEDULLA NEW ENGLAND JOURNAL OF MEDICINE GOLDMAN, S. H., Walker, S. R., Merigan, T. C., Gardner, K. D., Bull, J. M. 1966; 274 (18): 984-?

    View details for Web of Science ID A19667643000002

    View details for PubMedID 5909742

  • IN VITRO AND IN VIVO ANTIVIRAL ACTION OF AN INTERFERON-LIKE SUBSTANCE INDUCED BY TOXOPLASMA GONDII PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE Freshman, M. M., Merigan, T. C., REMINGTO, J. S., Brownlee, I. E. 1966; 123 (3): 862-?

    View details for Web of Science ID A19668738800063

    View details for PubMedID 4289528

  • INTERFERON AND UNINFECTED CELLS PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE Levy, H. B., Merigan, T. C. 1966; 121 (1): 53-?

    View details for Web of Science ID A19667282500016

    View details for PubMedID 4285509

  • ESSENTIAL ROLE OF SPECIFIC CONFORMATION IN ANTIGENICITY OF RIBONUCLEASE BIOCHEMISTRY Merigan, T. C., Potts, J. T. 1966; 5 (3): 910-?

    View details for Web of Science ID A19667421400015

    View details for PubMedID 4957906

  • PHYSICAL PROPERTIES OF HUMAN INTERFERON PREPARED IN VITRO AND IN VIVO VIROLOGY Merigan, T. C., Gregory, D. F., PETRALLI, J. K. 1966; 29 (4): 515-?

    View details for Web of Science ID A19668197100001

    View details for PubMedID 5945709

  • ACTION OF ENDOGENOUS INTERFERON AGAINST VACCINIA INFECTION IN CHILDREN LANCET PETRALLI, J. K., Merigan, T. C., Wilbur, J. R. 1965; 2 (7409): 401-?

    View details for Web of Science ID A19656747600002

    View details for PubMedID 14346758

  • CIRCULATING INTERFERON AFTER MEASLES VACCINATION NEW ENGLAND JOURNAL OF MEDICINE PETRALLI, J. K., Merigan, T. C., Wilbur, J. R. 1965; 273 (4): 198-?

    View details for Web of Science ID A19656637300005

    View details for PubMedID 14306336

  • PURIFIED INTERFERONS: PHYSICAL PROPERTIES AND SPECIES SPECIFICITY. Science Merigan, T. C. 1964; 145 (3634): 811-813

    View details for PubMedID 14163319

  • Studies on the antigenic combining sites in bacteriophage lysozyme. Annals of the New York Academy of Sciences Merigan, T. C., Dreyer, W. J. 1963; 103: 765-772

    View details for PubMedID 13934990

  • EFFECT OF INTRAVENOUSLY ADMINISTERED POSTERIOR PITUITARY EXTRACT ON HEMORRHAGE FROM BLEEDING ESOPHAGEAL VARICES - A CONTROLLED EVALUATION NEW ENGLAND JOURNAL OF MEDICINE Merigan, T. C., Davidson, C. S., PLOTKIN, G. R. 1962; 266 (3): 134-?

    View details for Web of Science ID A19628528B00015

    View details for PubMedID 14472813

  • TREATMENT OF HYPERCALCEMIA IN MULTIPLE MYELOMA - REPORT OF 2 PATIENTS ARCHIVES OF INTERNAL MEDICINE Merigan, T. C., Hayes, R. E. 1961; 107 (3): 389-?

    View details for Web of Science ID A19615556A00010

    View details for PubMedID 13769610

  • PLASMA FIBRINOLYSIS IN MAN - EFFECT OF CHYLOMICRONS DERIVED FROM DIFFERENT DIETARY FATS JOURNAL OF EXPERIMENTAL MEDICINE Farquhar, J. W., Merigan, T. C., Sokolow, M. 1961; 113 (3): 587-?

    Abstract

    The plasma fibrinolytic activity, measured in vitro, of 17 healthy normal young males was consistently and equally inhibited by prior ingestion of equal amounts of either a relatively saturated animal fat (butterfat) or a highly unsaturated vegetable fat (safflower oil). This effect was further studied by the addition of purified chylomicrons derived from ingestion of either butterfat, safflower oil, or egg yolk to an in vitro system. The inhibitory effect was quantitatively similar in all experiments despite wide variations in composition of the fed fat and pronounced differences in fatty acid composition of the lipids of the chylomicrons. It seems reasonable to suggest from our data that the proteins and the nonfatty acid portions of the chylomicron phospholipids may be important determinants of the inhibitory effect of chylomicrons on fibrinolysis.

    View details for Web of Science ID A19614809B00003

    View details for PubMedID 13698247

  • Thalassemia major. Thirty-five year survival, with obliterative pulmonary endarteritis and atypical bone changes. American journal of medicine Covey, M. C., Merigan, T. C., Petrakis, N. L., LUCIA, S. P. 1960; 28: 482-486

    View details for PubMedID 13812466

  • GASTROINTESTINAL BLEEDING WITH CIRRHOSIS - A STUDY OF 172 EPISODES IN 158 PATIENTS NEW ENGLAND JOURNAL OF MEDICINE Merigan, T. C., HOLLISTER, R. M., GRYSKA, P. F., STARKEY, G. W., Davidson, C. S. 1960; 263 (12): 579-585

    View details for Web of Science ID A1960ZW12600003

    View details for PubMedID 13769611

  • RETROBULBAR HEMORRHAGE IN A HEMOPHILIAC WITH IRREVERSIBLE LOSS OF VISION ARCHIVES OF OPHTHALMOLOGY Zimmerman, A., Merigan, T. C. 1960; 64 (6): 949-950

    View details for Web of Science ID A1960WF57600020

    View details for PubMedID 13788522

  • EFFECT OF CHYLOMICRONS ON THE FIBRINOLYTIC ACTIVITY OF NORMAL HUMAN PLASMA INVITRO CIRCULATION RESEARCH Merigan, T. C., Farquhar, J. W., Williams, J. H., Sokolow, M. 1959; 7 (2): 205-209

    View details for Web of Science ID A1959WK13400010

    View details for PubMedID 13629818

Conference Proceedings


  • Two double-blinded, randomized, comparative trials of 4 human immunodeficiency virus type 1 (HIV-1) envelope vaccines in HIV-1-infected individuals across a spectrum of disease severity: AIDS clinical trials groups 209 and 214 Schooley, R. T., Spino, C., Kuritzkes, D., Walker, B. D., Valentine, F. T., Hirsch, M. S., Cooney, E., Friedland, G., Kundu, S., Merigan, T. C., McElrath, M. J., Collier, A., Plaeger, S., Mitsuyasu, R., Kahn, J., Haslett, P., Uherova, P., DeGruttola, V., Chiu, S., Zhang, B., Jones, G., Bell, D., Ketter, N., Twadell, T., Chernoff, D., Rosandich, M. OXFORD UNIV PRESS INC. 2000: 1357-1364

    Abstract

    The potential role of human immunodeficiency virus type 1 (HIV-1)-specific immune responses in controlling viral replication in vivo has stimulated interest in enhancing virus-specific immunity by vaccinating infected individuals with HIV-1 or its components. These studies were undertaken to define patient populations most likely to respond to vaccination, with the induction of novel HIV-1-specific cellular immune responses, and to compare the safety and immunogenicity of several candidate recombinant HIV-1 envelope vaccines and adjuvants. New lymphoproliferative responses (LPRs) developed in <30% of vaccine recipients. LPRs were elicited primarily in study participants with a CD4 cell count >350 cells/mm(3) and were usually strain restricted. Responders tended to be more likely than nonresponders to have an undetectable level of HIV-1 RNA at baseline (P=.067). Induction of new cellular immune responses by HIV-1 envelope vaccines is a function of the immunologic stage of disease and baseline plasma HIV-1 RNA level and exhibits considerable vaccine strain specificity.

    View details for Web of Science ID 000090106000010

    View details for PubMedID 11023459

  • Clinical resistance patterns and responses to two sequential protease inhibitor regimens in saquinavir and reverse transcriptase inhibitor-experienced persons Lawrence, J., Schapiro, J., Winters, M., Montoya, J., Zolopa, A., Pesano, R., Efron, B., Winslow, D., Merigan, T. C. UNIV CHICAGO PRESS. 1999: 1356-1364

    Abstract

    The efficacy of sequential protease inhibitor therapy was studied in 16 human immunodeficiency virus (HIV) 1-infected persons in whom saquinavir with multiple nucleoside reverse transcriptase (RT) inhibitors (NRTI) had failed. Nelfinavir plus two NRTIs (new or continued) resulted in minimal (0.59 log RNA copies/mL) and transient (8 weeks) suppression of plasma HIV RNA levels. Rapid failure was surprisingly associated with baseline presence of protease gene mutation L90M (P=.04) in the absence of D30N and with RT mutations D67N (P<.01), K70R/S (P=.02), and K219Q/W/R/E (P<.01). Ten patients were subsequently switched to indinavir plus nevirapine and 2 NRTIs, resulting in a median 1.62 log reduction in plasma HIV RNA, with 3 patients maintaining 400 copies/mL for 24 weeks. These results suggest that nelfinavir may have limited utility after saquinavir failure, particularly without potent concomitant therapy. Combining an NRTI with a new protease inhibitor for rescue may improve response.

    View details for Web of Science ID 000080561100007

    View details for PubMedID 10228055

  • Use of PCR to measure HIV viral changes in drug-resistant genes in genital fluids Merigan, T. C. ELSEVIER IRELAND LTD. 1998: 177-185

    Abstract

    Our group has been studying HIV in genital fluids for several years. Our first findings demonstrated that both RNA PCR and proviral DNA PCR could be utilized to quantify virus within seminal interstitial fluid and non-spermatozoa mononuclear cells, respectively. It became clear that these techniques were more sensitive than viral culture and we also reported that both disease progression and treatment influenced sperm viral concentrations generally parallel to virus concentrations in blood. A more recent study from our group has demonstrated that mutations seen in the virus in the blood are seen in the seminal plasma viral as well as in the proviral forms within non-spermatozoa cells. We have also studied female patients for 2-month periods looking at RNA in plasma and cervical secretions, as well as proviral DNA in cervical and vaginal samples by polymerase chain reaction (PCR) amplification techniques. The HIV RNA levels again appears to be the most sensitive and well-related to systemic viral load. Thus, genital secretion of cell-free virus and cells containing proviral DNA in both sexes parallels systemic virus levels, is a site for measurement of transmission of drug-resistant virus and should be monitored in therapy as well as in pathogenesis studies.

    View details for Web of Science ID 000077946200014

    View details for PubMedID 10213309

  • Cytomegalovirus gB genotype distribution differs in human immunodeficiency virus - Infected patients and immunocompromised allograft recipients Rasmussen, L., Hong, C., Zipeto, D., Morris, S., Sherman, D., Chou, S. W., Miner, R., Drew, W. L., Wolitz, R., Dowling, A., Warford, A., Merigan, T. C. OXFORD UNIV PRESS INC. 1997: 179-184

    Abstract

    Cytomegalovirus isolates can be grouped into 4 gB and 2 gH genotypes. gB genotypes were studied in patients infected with human immunodeficiency virus (HIV) and in allograft transplantation recipients. In allograft recipients, the distribution of gB 1, -2, -3, and -4 in leukocytes and urine, respectively, was 36%, 21%, 43%, and 0% and 39%, 30%, 17%, and 13%. However, in leukocytes of HIV-infected patients with <100/microL CD4 cells, gB1 was found significantly less often than in allograft recipients (11% vs. 36%) but gB2 was more frequent (56% vs. 21%; P < .05). The decreased incidence of gBl and increased incidence of gB2 compared with allograft recipients was also seen in urine of HIV-infected patients and reflected the distribution seen in leukocytes. gB4 was found significantly more often (P < .05) in semen than in leukocytes of HIV-infected patients with < 100/microL CD4 cells. gB1-4 genotypes were similar in patients with < 100/microL CD4 cells with or without retinitis.

    View details for Web of Science ID A1997WA93700028

    View details for PubMedID 8985216

  • Prophylactic ganciclovir treatment reduces fungal as well as cytomegalovirus infections after heart transplantation Wagner, J. A., Ross, H., Hunt, S., Gamberg, P., Valantine, H., Merigan, T. C., Stinson, E. B. WILLIAMS & WILKINS. 1995: 1473-1477

    Abstract

    Cytomegalovirus (CMV) infection is associated with an increased incidence of other opportunistic infections in organ transplant recipients. Whether this is related to immunomodulating effects of CMV or independent of CMV but associated with a host risk factor common to both infections is unclear. The purpose of this study was to determine whether the reduction in CMV infections seen with prophylactic ganciclovir treatment after heart transplantation is associated with a reduced incidence of other opportunistic infections. Of 149 patients prospectively enrolled in a multicenter, randomized, double-blind, placebo-controlled trial of ganciclovir to prevent CMV disease, 74 patients enrolled at this center (33 control and 41 ganciclovir-treated) were retrospectively identified. All received prophylactic OKT-3 and standard 3 drug maintenance immunosuppressive therapy. Actuarial survival and rejection rates and incidence of opportunistic infections (bacterial, fungal, and protozoal) for the 2 treatment groups were determined and compared using Cox-Mantel analysis. CMV disease occurred 2.5 times more frequently in the control group. There were no significant differences in survival or rejection rates nor in bacterial or protozoal infection incidence between the 2 groups. Bacterial infections occurred in 54% of control and 39% of ganciclovir-treated patients (P = 0.18). There were significantly fewer fungal infections in the ganciclovir-treated group (7% vs. 27%, P = 0.0071). CMV and fungal infections were both significantly reduced in patients who received ganciclovir prophylaxis. This suggests that active CMV disease may be causally associated with the development of opportunistic fungal infections.

    View details for Web of Science ID A1995TN23000018

    View details for PubMedID 8545877

  • Individualization of therapy using viral markers Merigan, T. LIPPINCOTT-RAVEN PUBL. 1995: S41-S46

    Abstract

    Early intervention with a combination of drugs is generally accepted as the way forward in the management of HIV infection. In general, combination therapy should include agents that demonstrate additive or synergistic activity, do not have similar side-effect profiles, and avoid cross-resistance. Use of these criteria will no doubt lead to the development of more effective combinations. However, it is well known that patients respond to therapy in very different ways. A number of trials have provided clear examples of the individualized nature of patient responses to therapy and have also demonstrated that the use of measures such as viral load and CD4 cell count, in conjunction with phenotypic and genotypic characterization of emerging viral strains, may significantly enhance our ability to predict disease progression. A number of methods are becoming available to quantify accurately viral load, and new methodologies such as the Affymetrix chip-sequencing technique will allow quick detection of genotypic alterations known to be associated with disease progression, such as the appearance of resistance mutations. These developments now enable us to conduct clinical trials to assess the impact of an individualized approach to therapy, i.e., the changing of treatment regimens based on the identification of resistance markers, changes in viral load and CD4 cell count, and conversion from non-syncytium-inducing to syncytium-inducing phenotype. It is hoped that studies conducted in the near future will show that an approach of gaining maximal benefit from one treatment regimen before moving on to another, as a result of genotypic or viral load markers, will prevent destruction of the immune system and will ultimately prolong the well-being and survival of patients with HIV infection.

    View details for Web of Science ID A1995TX99800009

    View details for PubMedID 8595507

  • TREATMENT OF CYTOMEGALOVIRUS-INFECTION IN THE AIDS PATIENT Merigan, T. C. ELSEVIER SCIENCE INC. 1991: 122-125

    View details for Web of Science ID A1991FQ90900025

    View details for PubMedID 1648815

  • HUMAN CYTOMEGALOVIRUS GLYCOPROTEIN-RECEPTOR INTERACTIONS Rasmussen, L., Resta, S., Merigan, T. ELSEVIER SCIENCE INC. 1991: 60-63

    Abstract

    The HCMV envelope glycoprotein having a molecular weight of 86 kd, gH, has been shown to react with a 92 kd protein that can be extracted from HEL fibroblasts. This HCMV-gp86 membrane receptor appears to be present on the surface of both HCMV-permissive and HCMV-non-permissive cells, suggesting that there are factors in addition to viral attachment governing the intracellular replicative process. Another HCMV envelope glycoprotein (gp130/55; gB homologue) binds predominantly to a 31 kd protein with minor bands at 180, 96, and 90 kd. HCMV-gp86 does not bind to the principal gp130/55 receptor.

    View details for Web of Science ID A1991FQ90900014

    View details for PubMedID 1648838

  • CYTOMEGALOVIRUS - WHERE HAVE WE BEEN AND WHERE ARE WE GOING Merigan, T. C., Resta, S. UNIV CHICAGO PRESS. 1990: S693-S700

    Abstract

    Nearly 30 years have elapsed since Rowe and Weller and their colleagues discovered human cytomegalovirus (CMV). Because of its complex structure, long replicative cycle, low yield in vitro, and highly species-specific cell-substrate requirement, the cellular and molecular biologic analyses of human CMV have been slow, but recombinant DNA and monoclonal antibody technologies are bringing about rapid changes. Because of the long period of latency and wide range of disease presentations, epidemiologic and medical insights have also come slowly. However, the clinical events that occur during iatrogenic immunosuppression (transplantation and cancer therapy) and as a result of immunocompromise due to human immunodeficiency virus infection are currently promoting our understanding of the epidemiology of CMV disease and the definition of its clinical spectrum. Rapid diagnostic methods, antiviral drugs, and vaccines for CMV are becoming available. We may not yet understand completely the impact of this agent on the nonimmunosuppressed or aspects of its pathogenesis: e.g., the immune functions controlling recrudescence and the possibility of increased disease severity in those with no detectable immune defect. With the availability of new approaches, other issues should be clarified, such as the functions of host and virus involved in the mechanism of persistence.

    View details for Web of Science ID A1990EC14000002

    View details for PubMedID 2173098

  • CONCERNING MECHANISM OF ACTION OF INTERFERON Joklik, W. K., Merigan, T. C. NATL ACAD SCIENCES. 1966: 558-?

    View details for Web of Science ID A19668283500036

    View details for PubMedID 5229977

  • CHARACTERISTICS OF INTERFERON INDUCED IN VITRO AND IN VIVO BY A TRIC AGENT Merigan, T. C., Hanna, L. BLACKWELL SCIENCE INC. 1966: 421-?

    View details for Web of Science ID A19667880300030

    View details for PubMedID 4292459

  • INHIBITION OF TRIC AGENTS BY VIRUS-INDUCED INTERFERON Hanna, L., Merigan, T. C., JAWETZ, E. BLACKWELL SCIENCE INC. 1966: 417-?

    View details for Web of Science ID A19667880300029

    View details for PubMedID 5980548

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