Kevin Michael Alexander

All Publications

• High-Frequency Ultrasound Echocardiography to Assess Zebrafish Cardiac Function. Journal of visualized experiments : JoVE Evangelisti, A., Schimmel, K., Joshi, S., Shah, K., Fisch, S., Alexander, K. M., Liao, R., Morgado, I. 2020

  Abstract

  The zebrafish (Danio rerio) has become a very popular model organism in cardiovascular research, including human cardiac diseases, largely due to its embryonic transparency, genetic tractability, and amenity to rapid, high-throughput studies. However, the loss of transparency limits heart function analysis at the adult stage, which complicates modeling of age-related heart conditions. To overcome such limitations, high-frequency ultrasound echocardiography in zebrafish is emerging as a viable option. Here, we present a detailed protocol to assess cardiac function in adult zebrafish by non-invasive echocardiography using high-frequency ultrasound. The method allows visualization and analysis of zebrafish heart dimension and quantification of important functional parameters, including heart rate, stroke volume, cardiac output, and ejection fraction. In this method, the fish are anesthetized and kept underwater and can be recovered after the procedure. Although high-frequency ultrasound is an expensive technology, the same imaging platform can be used for different species (e.g., murine and zebrafish) by adapting different transducers. Zebrafish echocardiography is a robust method for cardiac phenotyping, useful in the validation and characterization of disease models, particularly late-onset diseases; drug screens; and studies of heart injury, recovery, and regenerative capacity.

  View details for DOI 10.3791/60976

  View details for PubMedID 32225163

• Bone Scintigraphy Imaging for Transthyretin Cardiac Amyloidosis: Still Much to Learn. JACC. Cardiovascular imaging Alexander, K. M., Witteles, R. M. 2020

  View details for DOI 10.1016/j.jcmg.2019.11.011

  View details for PubMedID 31954652

• Natural Compound Library Screening Identifies New Molecules for the Treatment of Cardiac Fibrosis and Diastolic Dysfunction. Circulation Schimmel, K., Jung, M., Foinquinos, A., San José, G., Beaumont, J., Bock, K., Grote-Levi, L., Xiao, K., Bär, C., Pfanne, A., Just, A., Zimmer, K., Ngoy, S., López, B., Ravassa, S., Samolovac, S., Janssen-Peters, H., Remke, J., Scherf, K., Dangwal, S., Piccoli, M. T., Kleemiss, F., Kreutzer, F. P., Kenneweg, F., Leonardy, J., Hobuß, L., Santer, L., Do, Q. T., Geffers, R., Braesen, J. H., Schmitz, J., Brandenberger, C., Müller, D. N., Wilck, N., Kaever, V., Bähre, H., Batkai, S., Fiedler, J., Alexander, K. M., Wertheim, B. M., Fisch, S., Liao, R., Diez, J., González, A., Thum, T. 2020

  Abstract

  Background: Myocardial fibrosis is a hallmark of cardiac remodeling and functionally involved in heart failure (HF) development, a leading cause of deaths worldwide. Clinically there is no therapeutic strategy available that specifically attenuates maladaptive responses of cardiac fibroblasts, the effector cells of fibrosis in the heart. Therefore, we aimed at the development of novel anti-fibrotic therapeutics based on natural-derived substance library screens for the treatment of cardiac fibrosis. Methods: Anti-fibrotic drug candidates were identified by functional screening of 480 chemically diverse natural compounds in primary human cardiac fibroblasts (HCFs), subsequent validation and mechanistic in vitro and in vivo studies. Hits were analyzed for dose-dependent inhibition of proliferation of HCFs, for modulation of apoptosis and extracellular matrix expression. In vitro findings were confirmed in vivo, using an angiotensin II (Ang II)-mediated murine model of cardiac fibrosis in both preventive and therapeutic settings, as well as in the Dahl salt sensitive rat model. To investigate the mechanism underlying the anti-fibrotic potential of the lead compounds, treatment-dependent changes in the noncoding RNAome in primary HCFs were analyzed by RNA-deep sequencing. Results: High-throughput natural compound library screening identified 15 substances with antiproliferative effects in HCFs. Using multiple in vitro fibrosis assays and stringent selection algorithms we identified the steroid bufalin (from Chinese toad venom) and the alkaloid lycorine (from Amaryllidaceae species) to be effective anti-fibrotic molecules both in vitro and in vivo leading to improvement in diastolic function in two hypertension-dependent rodent models of cardiac fibrosis. Administration at effective doses did not change plasma damage markers nor the morphology of kidney and liver, providing first toxicological safety data. By next-generation sequencing we identified the conserved microRNA (miR) miR-671-5p and downstream the antifibrotic selenoprotein P1 (SEPP1) as common effectors of the anti-fibrotic compounds. Conclusions: We identified the molecules bufalin and lycorine as drug candidates for therapeutic applications in cardiac fibrosis and diastolic dysfunction.

  View details for DOI 10.1161/CIRCULATIONAHA.119.042559

  View details for PubMedID 31948273

• Harnessing Cardiac Regeneration as a Potential Therapeutic Strategy for AL Cardiac Amyloidosis. Current cardiology reports Joshi, S., Evangelisti, A., Liao, R., Alexander, K. M. 2020; 22 (1): 1

  Abstract

  Cardiac regeneration has received much attention as a possible means to treat various forms of cardiac injury. This review will explore the field of cardiac regeneration by highlighting the existing animal models, describing the involved molecular pathways, and discussing attempts to harness cardiac regeneration to treat cardiomyopathies.Light chain cardiac amyloidosis is a degenerative disease characterized by progressive heart failure due to amyloid fibril deposition and light chain-mediated cardiotoxicity. Recent findings in a zebrafish model of light chain amyloidosis suggest that cardiac regenerative confers a protective effect against this disease. Cardiac regeneration remains an intriguing potential tool for treating cardiovascular disease. Degenerative diseases, such as light chain cardiac amyloidosis, may be particularly suited for therapeutic interventions that target cardiac regeneration. Further studies are needed to translate preclinical findings for cardiac regeneration into effective therapies.

  View details for DOI 10.1007/s11886-020-1252-3

  View details for PubMedID 31932992

• Diagnosis and Treatment of Cardiac Amyloidosis Related to Plasma Cell Dyscrasias. Cardiology clinics Alexander, K. M., Evangelisti, A., Witteles, R. M. 2019; 37 (4): 487–95

  Abstract

  Light chain amyloidosis is a deadly disease in which a monoclonal plasma cell dyscrasia produces misfolded immunoglobulin light chains (AL) that aggregate and form rigid amyloid fibrils. The amyloid deposits infiltrate one or more organs, leading to injury and severe dysfunction. The degree of cardiac involvement is a major driver of morbidity and mortality. Early diagnosis and treatment are crucial to prevent irreversible end-organ damage and improve overall survival. Treatment of AL cardiac amyloidosis involves eliminating the underlying plasma cell dyscrasia with chemotherapy and pursuing supportive heart failure management.

  View details for DOI 10.1016/j.ccl.2019.07.013

  View details for PubMedID 31587789

• Management of Cardiac Amyloidosis: Do's and Don'ts. The Canadian journal of cardiology Alexander, K. M., Witteles, R. M. 2019

  Abstract

  Cardiac amyloidosis is a potentially deadly disease characterized by progressive infiltration of amyloid fibrils, and it is increasingly recognized as an underdiagnosed but important cause of heart failure. Given its unique pathogenesis, there are key differences in the management of cardiac amyloidosis compared with other forms of heart failure. Moreover, the 2 common forms of cardiac amyloidosis, transthyretin and light-chain amyloidosis, are distinct entities with varying clinical manifestations and prognoses, leading to the need for tailored approaches to management. In the past decade, there have been many significant advances in the diagnosis and treatment of both forms of cardiac amyloidosis. For example, in selected cases, transthyretin cardiac amyloidosis can be diagnosed noninvasively with the use of bone scintigraphy imaging, avoiding the need for a biopsy. Effective, more targeted therapies have been developed for both transthyretin and light-chain amyloidosis. However, these treatments are much more effective in early stages of disease before significant end-organ amyloid deposition has occurred. Consequently, it is increasingly imperative that clinicians aggressively screen at-risk groups, identify early signs of disease, and initiate treatment. Finally, once thought to be ill advised, heart transplantation should be considered in carefully selected patients with end-stage cardiac amyloidosis, because transplant outcomes in these patients is now similar to other those for other cardiomyopathies. Given these and other recent changes in clinical practice, this article discusses several key considerations for the clinical care of patients with cardiac amyloidosis.

  View details for DOI 10.1016/j.cjca.2019.10.032

  View details for PubMedID 32033795

• Trends and causes of hospitalizations in patients with amyloidosis. Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis Patil, N., Arora, S., Qamar, A., Strassle, P. D., Alexander, K. M., Fatima, A., Maurer, M. S., Grodin, J. L., Pandey, A. 2019: 1–2

  View details for DOI 10.1080/13506129.2019.1618261

  View details for PubMedID 31172802

• Emerging Therapies for Transthyretin Cardiac Amyloidosis. Current treatment options in cardiovascular medicine Alexander, K. M., Evangelisti, A., Witteles, R. M. 2019; 21 (8): 40

  Abstract

  Transthyretin cardiac amyloidosis is an underdiagnosed, undertreated disease which is associated with significant morbidity and mortality. This review will discuss the recent advancements in novel therapies for transthyretin amyloidosis.In recent phase 3 clinical trials, transthyretin stabilizers (tafamidis) and transthyretin silencers (patisiran and inotersen) have proven to be effective therapies for various forms of transthyretin amyloidosis. Understanding the recent and upcoming clinical trials for transthyretin amyloidosis will be important for improving the management of this challenging disease.

  View details for DOI 10.1007/s11936-019-0743-2

  View details for PubMedID 31309347

• True, true unrelated? Coexistence of Waldenstrom's macroglobulinemia and cardiac transthyretin Amyloidosis. Haematologica Singh, A., Geller, H. I., Alexander, K. M., Padera, R. F., Mitchell, R. N., Dorbala, S., Castillo, J. J., Falk, R. H. 2018

  View details for PubMedID 29674499

• Mortality from Heart Failure and Dementia in the United States: CDC WONDER 1999-2016. Journal of cardiac failure Vuong, J. T., Jacob, S. A., Alexander, K. M., Singh, A., Liao, R., Desai, A. S., Dorbala, S. 2018

  Abstract

  Heart failure and dementia are diseases of the elderly that result in billions of dollars in annual healthcare expenditure. With the aging of the United States population, and increasing evidence of shared risk factors, there is a need to understand the conditions' shared contributions to nationwide mortality. The objectives of our study are to estimate the burden of mortality from heart failure and dementia and characterize the demographics of affected individuals.This is a retrospective study using National Vital Statistics Data from 1999-2016 provided by the Centers for Disease Control and ICD-10 codes for heart failure and dementia defined by the Medicare Chronic Conditions Data Warehouse. From 1999 to 2016, deaths contributed by heart failure and dementia totaled 214,706 and comprised 4.00% of all heart failure deaths and 9.04% of all dementia deaths. Women were more affected than men, with higher age-adjusted mortality rates (per 1,000,000 person-years): 38.67, 95% CI: 38.47-38.87 vs. 32.90, 95% CI: 32.65-33.15, p<0.001. Whites were affected more than Blacks, with age-adjusted mortality rates (per 1,000,000 person-years): 38.00, 95% CI: 37.83-38.16 vs. 31.06, 95% CI: 30.54-31.59, p<0.001. However, under the age of 65 years, higher crude mortality rates (per 1,000,000 person-years) were reported in men (0.20, 95% CI 0.18-0.22) compared with women (0.15, 95% CI 0.13-0.16, p<0.001).This study provides insight into temporal trends and nationwide mortality rates reported for heart failure and dementia. Our results suggest a disproportionate burden on populations over 85 years, Whites, and women.

  View details for PubMedID 30471348

• Stage A Heart Failure: Identification and Management of Heart Failure Risk Factors Encyclopedia of Cardiovascular Research and Medicine Alexander, K. M., Nayor, M. 2018: 446–455

  View details for DOI https://doi.org/10.1016/B978-0-12-809657-4.64288-6

• Randomized Evaluation of Heart Failure With Preserved Ejection Fraction Patients With Acute Heart Failure and Dopamine: The ROPA-DOP Trial. JACC. Heart failure Sharma, K., Vaishnav, J., Kalathiya, R., Hu, J. R., Miller, J., Shah, N., Hill, T., Sharp, M., Tsao, A., Alexander, K. M., Gupta, R., Montemayor, K., Kovell, L., Chasler, J. E., Lee, Y. J., Fine, D. M., Kass, D. A., Weiss, R. G., Thiemann, D. R., Ndumele, C. E., Schulman, S. P., Russell, S. D. 2018

  Abstract

  This study sought to compare a continuous infusion diuretic strategy versus an intermittent bolus diuretic strategy, with the addition of low-dose dopamine (3 μg/kg/min) in the treatment of hospitalized patients with heart failure with preserved ejection fraction (HFpEF).HFpEF patients are susceptible to development of worsening renal function (WRF) when hospitalized with acute heart failure; however, inpatient treatment strategies to achieve safe and effective diuresis in HFpEF patients have not been studied to date.In a prospective, randomized, clinical trial, 90 HFpEF patients hospitalized with acute heart failure were randomized within 24 h of admission to 1 of 4 treatments: 1) intravenous bolus furosemide administered every 12 h; 2) continuous infusion furosemide; 3) intermittent bolus furosemide with low-dose dopamine; and 4) continuous infusion furosemide with low-dose dopamine. The primary endpoint was percent change in creatinine from baseline to 72 h. Linear and logistic regression analyses with tests for interactions between diuretic and dopamine strategies were performed.Compared to intermittent bolus strategy, the continuous infusion strategy was associated with higher percent increase in creatinine (continuous infusion: 16.01%; 95% confidence interval [CI]: 8.58% to 23.45% vs. intermittent bolus: 4.62%; 95% CI: -1.15% to 10.39%; p = 0.02). Low-dose dopamine had no significant effect on percent change in creatinine (low-dose dopamine: 12.79%; 95% CI: 5.66% to 19.92%, vs. no-dopamine: 8.03%; 95% CI: 1.44% to 14.62%; p = 0.33). Continuous infusion was also associated with greater risk of WRF than intermittent bolus (odds ratio [OR]: 4.32; 95% CI: 1.26 to 14.74; p = 0.02); no differences in WRF risk were seen with low-dose dopamine. No significant interaction was seen between diuretic strategy and low-dose dopamine (p > 0.10).In HFpEF patients hospitalized with acute heart failure, low-dose dopamine had no significant impact on renal function, and a continuous infusion diuretic strategy was associated with renal impairment. (Diuretics and Dopamine in Heart Failure With Preserved Ejection Fraction [ROPA-DOP]; NCT01901809).

  View details for DOI 10.1016/j.jchf.2018.04.008

  View details for PubMedID 30098962

• Geographic Disparities in Reported US Amyloidosis Mortality From 1979 to 2015: Potential Underdetection of Cardiac Amyloidosis. JAMA cardiology Alexander, K. M., Orav, J., Singh, A., Jacob, S. A., Menon, A., Padera, R. F., Kijewski, M. F., Liao, R., Di Carli, M. F., Laubach, J. P., Falk, R. H., Dorbala, S. 2018

  Abstract

  Cardiac amyloidosis is an underdiagnosed disease and is highly fatal when untreated. Early diagnosis and treatment with the emerging novel therapies significantly improve survival. A comprehensive analysis of amyloidosis-related mortality is critical to appreciate the nature and distribution of underdiagnosis and improve disease detection.To evaluate the temporal and regional trends in age-adjusted amyloidosis-related mortality among men and women of various races/ethnicities in the United States.In this observational cohort study, death certificate information from the Centers for Disease Control and Prevention's Wide-ranging ONline Data for Epidemiologic Research database and the National Vital Statistics System from 1979 to 2015 was analyzed. A total of 30 764 individuals in the United States with amyloidosis listed as the underlying cause of death and 26 591 individuals with amyloidosis listed as a contributing cause of death were analyzed.Region of residence.Age-adjusted mortality rate from amyloidosis per 1 000 000 population stratified by year, sex, race/ethnicity, and state and county of residence.Of the 30 764 individuals with amyloidosis listed as the underlying cause of death, 17 421 (56.6%) were men and 27 312 (88.8%) were 55 years or older. From 1979 to 2015, the reported overall mean age-adjusted mortality rate from amyloidosis as the underlying cause of death doubled from 1.77 to 3.96 per 1 000 000 population (2.32 to 5.43 in men and 1.35 to 2.80 in women). Black men had the highest mortality rate (12.36 per 1 000 000), followed by black women (6.48 per 1 000 000). Amyloidosis contributed to age-adjusted mortality rates as high as 31.73 per 1 000 000 in certain counties. Most southern states reported the lowest US mortality rates despite having the highest proportions of black individuals.The increased reported mortality over time and in proximity to amyloidosis centers more likely reflects an overall increase in disease diagnosis rather than increased lethality. The reported amyloidosis mortality is highly variable in different US regions. The lack of higher reported mortality rates in states with a greater proportion of black residents suggests underdiagnosis of amyloidosis, including cardiac forms of the disease, in many areas of the United States. Better understanding of the determinants of geographic and racial disparity in the reporting of amyloidosis deaths are warranted.

  View details for PubMedID 30046835

• Association Between Ruptured Distal Biceps Tendon and Wild-Type Transthyretin Cardiac Amyloidosis. JAMA Geller, H. I., Singh, A., Alexander, K. M., Mirto, T. M., Falk, R. H. 2017; 318 (10): 962–63

  View details for PubMedID 28898370

  View details for PubMedCentralID PMC5818850

• Novel pharmacotherapies for cardiac amyloidosis. Pharmacology & therapeutics Alexander, K. M., Singh, A., Falk, R. H. 2017; 180: 129–38

  Abstract

  Amyloidosis refers to a range of protein misfolding disorders that can cause organ dysfunction through progressive fibril deposition. Cardiac involvement often leads to significant morbidity and mortality and increasingly has been recognized as an important cause of heart failure. The two main forms of cardiac amyloidosis, light chain (AL) and transthyretin (ATTR) amyloidosis, have distinct mechanisms of pathogenesis. Recent insights have led to the development of novel pharmacotherapies with the potential to significantly impact each disease. This review will summarize the preclinical and clinical data for these emerging treatments for AL and ATTR amyloidosis.

  View details for PubMedID 28648829

  View details for PubMedCentralID PMC5832446

• Phosphorylation of Src by phosphoinositide 3-kinase regulates beta-adrenergic receptor-mediated EGFR transactivation. Cellular signalling Watson, L. J., Alexander, K. M., Mohan, M. L., Bowman, A. L., Mangmool, S., Xiao, K., Naga Prasad, S. V., Rockman, H. A. 2016; 28 (10): 1580-1592

  Abstract

  β2-Adrenergic receptors (β2AR) transactivate epidermal growth factor receptors (EGFR) through formation of a β2AR-EGFR complex that requires activation of Src to mediate signaling. Here, we show that both lipid and protein kinase activities of the bifunctional phosphoinositide 3-kinase (PI3K) enzyme are required for β2AR-stimulated EGFR transactivation. Mechanistically, the generation of phosphatidylinositol (3,4,5)-tris-phosphate (PIP3) by the lipid kinase function stabilizes β2AR-EGFR complexes while the protein kinase activity of PI3K regulates Src activation by direct phosphorylation. The protein kinase activity of PI3K phosphorylates serine residue 70 on Src to enhance its activity and induce EGFR transactivation following βAR stimulation. This newly identified function for PI3K, whereby Src is a substrate for the protein kinase activity of PI3K, is of importance since Src plays a key role in pathological and physiological signaling.

  View details for DOI 10.1016/j.cellsig.2016.05.006

  View details for PubMedID 27169346

  View details for PubMedCentralID PMC4980165

• AL (Light-Chain) Cardiac Amyloidosis: A Review of Diagnosis and Therapy. Journal of the American College of Cardiology Falk, R. H., Alexander, K. M., Liao, R., Dorbala, S. 2016; 68 (12): 1323-1341

  Abstract

  The amyloidoses are a group of protein-folding disorders in which ≥1 organ is infiltrated by proteinaceous deposits known as amyloid. The deposits are derived from 1 of several amyloidogenic precursor proteins, and the prognosis of the disease is determined both by the organ(s) involved and the type of amyloid. Amyloid involvement of the heart (cardiac amyloidosis) carries the worst prognosis of any involved organ, and light-chain (AL) amyloidosis is the most serious form of the disease. The last decade has seen considerable progress in understanding the amyloidoses. In this review, current and novel approaches to the diagnosis and treatment of cardiac amyloidosis are discussed, with particular reference to AL amyloidosis in the heart.

  View details for DOI 10.1016/j.jacc.2016.06.053

  View details for PubMedID 27634125

• V122I TTR Cardiac Amyloidosis in Patients of African Descent: Recognizing a Missed Disease or the Dog That Didn't Bark? CIRCULATION-HEART FAILURE Alexander, K. M., Falk, R. H. 2016; 9 (9)

  View details for DOI 10.1161/CIRCHEARTFAILURE.116.003489

  View details for Web of Science ID 000384460800011

  View details for PubMedID 27618856

• Grim Messenger: Virchow's Node Presenting with Virchow's Triad AMERICAN JOURNAL OF MEDICINE Alexander, K. M., Vaduganathan, M., Qamar, A., Gerhard-Herman, M. D. 2016; 129 (9): 948-951

  View details for DOI 10.1016/j.amjmed.2016.05.009

  View details for Web of Science ID 000382309900036

  View details for PubMedID 27267288

• Response by Alexander et al to Letters Regarding Article, "A Shocking Development in a Young Male Athlete With Chest Pain" CIRCULATION Alexander, K. M., Veillet-Chowdhury, M. R., Macintyre, C. J., Loscalzo, J., Bhatt, D. L. 2016; 134 (4): E22-E23

  View details for DOI 10.1161/CIRCULATIONAHA.116.023204

  View details for Web of Science ID 000380136700003

  View details for PubMedID 27462059

• Utility of multimodality imaging in myopericarditis with aortitis. Journal of nuclear cardiology Qamar, A., Veeranna, V., Fatima, A., Alexander, K. M., Di Carli, M. F., Bonaca, M. P., Steigner, M., Dorbala, S. 2016: -?

  View details for PubMedID 27174190

• A Shocking Development in a Young Male Athlete With Chest Pain CIRCULATION Alexander, K. M., Veillet-Chowdhury, M. R., Macintyre, C. J., Loscalzo, J., Bhatt, D. L. 2016; 133 (8): 756-763

  View details for DOI 10.1161/CIRCULATIONAHA.115.019127

  View details for Web of Science ID 000371490400009

  View details for PubMedID 26903018

• Mechanical circulatory support for advanced heart failure. Current treatment options in cardiovascular medicine Patel, C. B., Alexander, K. M., Rogers, J. G. 2010; 12 (6): 549-565

  Abstract

  Both acute and chronic systolic heart failure can progress to an advanced phase, resulting in stage D heart failure and even cardiogenic shock. Despite significant progress in the treatment of systolic heart failure using medical and device therapies, this terminal phase continues to be prevalent and associated with unacceptably high morbidity and mortality. Given the inability to offer cardiac transplantation to the majority of those presenting with advanced heart failure, alternative strategies for cardiac replacement therapy are often required. Although there has been interest in using mechanical devices to support the circulation since the advent of cardiopulmonary bypass, it is only in the past 20 years that ventricular assist devices (VAD) have become viable options for therapy. Indeed, we are now entering an era where circulatory assist devices are being used not only to temporarily support patients with post-cardiotomy shock, but also as a long-term treatment in ambulatory heart failure patients. Furthermore, we are now able to utilize data from multicenter trials and registries to guide treatment decisions. These data have clearly shown that VADs improve survival and quality of life in patients with advanced heart failure when implanted as a temporary measure (bridge to recovery and bridge to transplant) or as long-term support (destination therapy). However, with a growing heart failure population there is much work to be done to improve VAD technology, patient selection, post-implantation management, and to define the optimal role for assist devices in the management of systolic heart failure. We are also in the nascent stages of fully understanding the impact of mechanical support on the failing myocardium, and developing research methodologies to study novel therapies in tandem with VADs to facilitate ventricular recovery. These important questions are currently being addressed in ongoing clinical trials, registry analyses, and translational research endeavors.

  View details for DOI 10.1007/s11936-010-0093-6

  View details for PubMedID 21063932

• A V3 Loop-Dependent gp120 Element Disrupted by CD4 Binding Stabilizes the Human Immunodeficiency Virus Envelope Glycoprotein Trimer JOURNAL OF VIROLOGY Xiang, S., Finzi, A., Pacheco, B., Alexander, K., Yuan, W., Rizzuto, C., Huang, C., Kwong, P. D., Sodroski, J. 2010; 84 (7): 3147-3161

  Abstract

  Human immunodeficiency virus (HIV-1) entry into cells is mediated by a trimeric complex consisting of noncovalently associated gp120 (exterior) and gp41 (transmembrane) envelope glycoproteins. The binding of gp120 to receptors on the target cell alters the gp120-gp41 relationship and activates the membrane-fusing capacity of gp41. Interaction of gp120 with the primary receptor, CD4, results in the exposure of the gp120 third variable (V3) loop, which contributes to binding the CCR5 or CXCR4 chemokine receptors. We show here that insertions in the V3 stem or polar substitutions in a conserved hydrophobic patch near the V3 tip result in decreased gp120-gp41 association (in the unliganded state) and decreased chemokine receptor binding (in the CD4-bound state). Subunit association and syncytium-forming ability of the envelope glycoproteins from primary HIV-1 isolates were disrupted more by V3 changes than those of laboratory-adapted HIV-1 envelope glycoproteins. Changes in the gp120 beta2, beta19, beta20, and beta21 strands, which evidence suggests are proximal to the V3 loop in unliganded gp120, also resulted in decreased gp120-gp41 association. Thus, a gp120 element composed of the V3 loop and adjacent beta strands contributes to quaternary interactions that stabilize the unliganded trimer. CD4 binding dismantles this element, altering the gp120-gp41 relationship and rendering the hydrophobic patch in the V3 tip available for chemokine receptor binding.

  View details for DOI 10.1128/JVI.02587-09

  View details for Web of Science ID 000275307400002

  View details for PubMedID 20089638

  View details for PubMedCentralID PMC2838131