Comparative studies of progressive and non-progressive AIDS virus infections in human and non-human primates

Since its discovery in the 1980\u27s, HIV infection has expanded into pandemic proportions and is responsible for a staggering amount of death and disease worldwide. Although antiretroviral therapy has drastically reduced the morbidity and mortality associated with HIV infection, it is not a cure and requires life-long adherence to avoid disease progression. As such, sustained efforts into studying HIV pathogenesis are necessary to develop better therapies. An integrated approach to studying HIV pathogenesis involves using various progressive and non-progressive models of HIV and SIV infection comparatively, and this approach has guided the work in this thesis. Sooty mangabeys (SMs) are examples of SIV natural hosts for whom SIV infection is characteristically non-progressive, and have been studied extensively to elucidate features associated with protection from disease. However, these studies have been cross-sectional or experimental in nature. Therefore, we conducted a five-year longitudinal analysis to characterize the clinical and immunologic dynamics of naturally SIV-infected SMs. We found that natural SIV infection in SMs is associated with slowly declining CD4+ T cell counts, stable levels of viremia, and consistently low T cell activation. Low CCRS expression on CD4+ T cells is another feature associated with SIV natural hosts. This is intriguing, since the reduction in CD4+CCR5+ viral target cells does not prevent persistently high viral loads in SIV-infected natural hosts. As such, we hypothesized that low CCR5 expression in SIV natural hosts contributes to reduced activated T cell trafficking and low immune activation, and we tested this hypothesis in a non-natural host, the rhesus macaque. We found that blocking CCR5 in vivo resulted in an altered distribution of CCR5+ and CD25+ T cells in blood and tissues that may reduce inflammation during progressive SIV infection. Finally, human Viremic Non-Progressors (VNPs) represent a largely uncharacterized HIV infection phenotype that clinically resembles SIV infection in natural hosts with high viral loads and maintenance of healthy CD4+ T cell counts. We conducted a preliminary immunophenotyping study that revealed trends in lower T cell activation in VNPs as compared to HIV normal progressors. In conclusion, the work presented here should assist future investigations in comparative AIDS research