Ndung'u, Peter Thumbi.Radebe, Mopo.2016-08-292016-08-2920152015http://hdl.handle.net/10413/13299Ph. D University of KwaZulu-Natal, Durban 2015.Evidence suggests that CD8+ T-­‐cells play a major role in the control of HIV-­‐1 viremia and apply significant immune pressure on HIV-­‐1 replication. However, the presence of virus-­‐specific CD8+ T-­‐cells in individuals with varying levels of viral control suggests that CD8+ T-­‐cells may differ in their antiviral function or efficacy. The mechanisms underlying differences in the control of viremia, particularly the reasons why particular individuals experience more effective acute viremia resolution, which is a good correlate of the subsequent rate of disease progression, are still not well understood. In order to uncover some of the features of CD8+ T-­‐cell subsets responsible for the control of HIV replication, particularly during the critical early infection phase, we investigated the patterns and features of HIV-­‐1-­‐specific CD8+ T-­‐ cell responses during acute and primary HIV-­‐1 infection and their association with viral control. We also sought to determine the impact of acute phase immune activation on the acute HIV-­‐1-­‐specific CD8+ T-­‐cell response and on disease progression. We hypothesized that protein-­‐specific and epitope-­‐specific immunodominance patterns during the first 12 weeks of HIV-­‐1 infection are associated with subsequent disease progression. Our data show the presence of HIV-­‐1 specific CD8+ T-­‐cells with limited breadth during acute HIV-­‐1 infection and also demonstrate that the magnitude and breadth of interferon gamma (IFN-­‐γ) ELISPOT assay responses measured within 12 weeks post-­‐infection are unrelated to the course of disease in the first year of infection. During the first weeks of infection Nef protein was most frequently recognized by T-­‐ xv cells and was the target for the earliest response. Although initially subdominant, there was a broadening of the Gag-­‐specific T-­‐cell immune response such that these responses became immunodominant by one year post infection. The broadening and preservation of early Gag–specific T-­‐cell responses during the follow up period was associated with better control of viremia and lower viral load set point. Although many of the acute/early HIV-­‐1-­‐specific IFN-­‐γ enzyme linked immunospot assay (ELISPOT) CD8+ T-­‐cell responses targeting Gag and Pol persisted, the majority of acute and early T-­‐cell responses targeting Env, Nef and other regulatory proteins waxed and waned over time and could not be detected at the last time point evaluated. Some of the early T-­‐cell responses which where no longer detectable when using overnight ELISPOT assay were detectable when PBMCs were stimulated with corresponding peptides and cultured for 10 days before measuring IFN-­‐γ secretion via the ELISPOT assay. The presence of these cultured ELISPOT central memory type T-­‐cell responses targeting epitopes in Pol, Env, Nef, Regulatory and Accessory proteins were not significantly associated with viral set point. However, cultured ELISPOT Gag-­‐specific responses correlated with low plasma viremia, thus further providing evidence for the favourable role of Gag-­‐specific T-­‐cell responses in the control of viral replication. We also show that three cytokines IL-­‐10, IP-­‐10 and IL-­‐ 12 were associated with changes in viral load set point and/or CD4+ T-­‐cell dynamics during the first year of HIV-­‐1 infection. Interestingly, the activation of the PD-­‐1 inhibitory pathway in acute HIV-­‐1 infection was associated with a slower disease progression.en-ZAHIV infections--Immunological aspects.HIV infections--Complications.T cells--Immunology.Theses--Immunology.HIV-1 infection.Viral control.Thesis