Genome Technology Center

How natural host species avoid CD4+ T cell depletion: Insights into the pathogenesis of HIV

Chan, M. L. 1, Petravic, J. 1, Ortiz, A. 2, Engram, J. 2, Paiardini, M. 2, Cromer, D. 3, Silvestri, G. 2, 4, Davenport, M. P. 1

  1. Complex Systems in Biology Group, Centre for Vascular Research, University of New South Wales, Kensington, NSW, Australia.
  2. Department of Pathology and Laboratory Medicine, University of Pennsylvania, PA, USA
  3. Department of Mathematics and Centre for Integrative Systems Biology, Imperial College London, London, UK.
  4. Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA

Human immunodeficiency virus (HIV) infection involves the progressive decline of CD4+ T lymphocytes, resulting in severe immune deficiency. This in turn leads to opportunistic infections and cancers characteristic of AIDS, and eventually death. HIV is derived from simian immunodeficiency virus (SIV) which infects primates. It has been observed that natural hosts of SIV, such as Sooty Mangabeys, are largely asymptomatic when infected. This is sharply contrasted with non-natural hosts of SIV, such as Rhesus Macaques, and untreated HIV-infected individuals, who experience progressive depletion of CD4+ T cells in the blood and lymphoid tissues, and go on to develop AIDS. Currently, the lack of disease progression in natural hosts of SIV is still not clearly understood. A better understanding of why SIV is not pathogenic in natural hosts will therefore provide valuable insights into the pathogenesis of AIDS in HIV-infected individuals. Experimental data show that as CD4+ T cells are depleted during infection, there is an increase in the proliferation rate of the remaining CD4+ T cells [as measured by Ki67 expression]. However, Sooty Mangabeys show only a small increase in the fraction of proliferating CD4+ T cells compared to larger increases in Rhesus Macaques and HIV-infected individuals. This suggests that disease progression is associated with the marked differences in the homeostatic proliferation of CD4+ T cells in response to CD4+ T cell depletion. In our study, we have developed a model that demonstrates the relationship between proliferation and disease outcome to help us understand why SIV is not pathogenic in Sooty Mangabeys, while in SIV-challenged Rhesus Macaques and HIV-infected individuals, infection leads to AIDS. Modelling of this relationship suggests that a slower, but still effective, homeostatic response to CD4+ T cell depletion in non-pathogenic SIV infection paradoxically leads to preservation of higher CD4+ T cell levels during chronic infection. The results indicate that one of the key mechanisms by which natural hosts have adapted to SIV infection is by attenuating their proliferative homeostatic response to chronic CD4+ T cell depletion.

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