One of the factors limiting the success of CDS T cell responses in controlling HIV lies within thepropensity of HIV to escape through the accumulation of viral variants. Rapid escape fromimmunodominant CDS responses, or transmission of CTL escape variants within these epitopes, may beassociated with the inability of the immune system to effectively contain early viral replication. Recentstudies 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 Tcell pressures. However, our understanding of the impact that viral escape from early immunodominant Tcell responses has on early immune control remains limited.In parallel, studies have now illustrated the propensity for some CTL escape mutations to revertupon transmission, some of which have now been shown to impart a cost to viral replication capacity, orviral 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 acuteinfection or the impact of early CTL escape mutations on viral fitness. Together these data suggest thatthe rate of viral sequence escape and reversion may serve as surrogate markers for the selectivepressure 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 abrogateimmunodominant CDS T cell responses, and to identify early CTL escape mutations. In addition we willassess viral replication capacity over the course of infection to characterize the contribution of viral fitnessto early immune control. By extension we will also assess the impact of specific CTL escape mutationson viral fitness. These studies will provide crucial new information on the contribution of early evolutionarychanges in HIV on immune control and pathogenesis. We will:1. Identify rapidly evolving and transmitted mutations within CDS T cell epitopes and determine theirimpact on normal immunodominance patterns of CD8+ T cell responses.2. Identify rapidly reverting residues following acute HIV-1 infection, and the impact of those transmittedmutations within immunodominant CDS epitopes on viral fitness.3. Determine the viral fitness of transmitted HIV-1 strains and its contribution to the early containment ofHIV.
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