Analysis of epitope-specific HIV CD8+ T cell responses elicited during early HIV-1 infection and their association with viral control

Thesis (Ph.D.)--University of Washington, 2012The enormity of global human immunodeficiency virus type 1 (HIV)/acquired immunodeficiency syndrome (AIDS) pandemic underscores the urgency to develop a safe, effective and accessible prophylactic AIDS vaccine. Multiple lines of evidence in humans and animal models have shown that HIV-1-specific CD8+ cytotoxic T lymphocytes (CTL) are important in controlling and preventing HIV infection. However, the precise qualities of effective epitope-specific CD8+ CTL responses that may be responsible for control remain unclear. Several vaccine strategies have been designed to elicit CD8+ T cell responses against HIV. Previous T cell based vaccine candidates that have failed to offer protection and HIV control primarily induced HIV-1-specific T cells that targeted variable regions of HIV-1. Genetic studies have shown an association between specific human leukocyte antigens (HLAs), (notably HLA-B*27 and -B*57 allele groups) and slower rates of disease progression in the absence of anti-retroviral therapy (ART). HIV-1-specific CD8+ T cells restricted by these HLA alleles are dominant early in infection in individuals expressing these alleles, and predominantly target conserved regions of Gag. These data suggest that an effective T-cell based immunogen should contain conserved regions of HIV-1 as it will increase the likelihood that CD8+ T cells will recognize incoming viral species of diverse clades and decrease the likelihood of rapid escape variants against the recognized epitopes. We extend these observations to comprehensively identify all CD8+ T cell responses that are elicited during early infection. The central goal of this dissertation is to determine if conservation of the epitopes targeted during early HIV-1-infection play an important role on viral control. Here we demonstrate that individuals possessing CD8+ T cells recognizing conserved epitopes of the virus have lower viral load set point than those recognizing only variable epitopes. Collectively, our results imply that the next-generation of T cell based vaccines should focus on strategies that can induce CD8+ T cell responses specifically to conserved regions of HIV-1