Identifying Acute Phase CTL Escape Mutations and their Impact on HIV Fitness

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One of the factors limiting the success of CDS T cell responses in controlling HIV lies within the propensity of HIV to escape through the accumulation of viral variants. Rapid escape from immunodominant CDS responses, or transmission of CTL escape variants within these epitopes, may be associated with the inability of the immune system to effectively contain early viral replication. Recent studies have solidified our understanding that acute phase escape is a hallmark of HIV and SIV infection, and that a majority of amino acid substitutions arising over the course of infection are driven by CDS T cell pressures. However, our understanding of the impact that viral escape from early immunodominant T cell responses has on early immune control remains limited. In parallel, studies have now illustrated the propensity for some CTL escape mutations to revert upon transmission, some of which have now been shown to impart a cost to viral replication capacity, or viral fitness, revealing a greater appreciation of the contribution of viral fitness to the control of HIV. However, little is known regarding the contribution of viral fitness to the control of HIV during acute infection or the impact of early CTL escape mutations on viral fitness. Together these data suggest that the rate of viral sequence escape and reversion may serve as surrogate markers for the selective pressure applied by particular CDS T cell responses and the fitness cost of CTL escape mutations, respectively. The aim of this proposal is to identify transmitted CTL escape mutations that abrogate immunodominant CDS T cell responses, and to identify early CTL escape mutations. In addition we will assess viral replication capacity over the course of infection to characterize the contribution of viral fitness to early immune control. By extension we will also assess the impact of specific CTL escape mutations on viral fitness. These studies will provide crucial new information on the contribution of early evolutionary changes in HIV on immune control and pathogenesis. We will: 1. Identify rapidly evolving and transmitted mutations within CDS T cell epitopes and determine their impact on normal immunodominance patterns of CD8+ T cell responses. 2. Identify rapidly reverting residues following acute HIV-1 infection, and the impact of those transmitted mutations within immunodominant CDS epitopes on viral fitness. 3. Determine the viral fitness of transmitted HIV-1 strains and its contribution to the early containment of HIV.