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

限制CDS T细胞反应成功控制HIV的因素之一在于 艾滋病毒通过病毒变种的积累而逃逸的倾向。迅速逃脱 免疫显性CDS反应或CTL逃逸变异体在这些表位内的传递可能是 与免疫系统无法有效遏制早期病毒复制有关。近期 研究巩固了我们的理解，即急性逃逸是艾滋病毒和SIV感染的一个标志， 在感染过程中产生的大多数氨基酸替换是由CDS T驱动的 细胞压力。然而，我们对病毒逃避早期免疫优势T细胞的影响的理解 细胞反应对早期免疫控制的影响仍然有限。 与此同时，现在的研究表明，一些CTL逃逸突变有逆转的倾向 在传播时，其中一些现在已被证明会给病毒复制能力带来成本，或者 病毒适合性，揭示了对病毒适合性对控制艾滋病毒的贡献的更大赞赏。 然而，对于病毒适合性在急性发作期间对艾滋病毒控制的贡献，我们知之甚少。 感染或早期CTL逃逸突变对病毒适应性的影响。这些数据加在一起表明 病毒序列逃逸和返回率可作为选择性 特定CDS T细胞反应施加的压力和CTL逃逸突变的适应成本， 分别进行了分析。 这项建议的目的是识别传递的CTL逃逸突变，这些突变可以消除 免疫显性CDS T细胞反应，并识别早期CTL逃逸突变。此外，我们还将 评估感染过程中的病毒复制能力，以表征病毒适合性的贡献 到早期的免疫控制。此外，我们还将评估特定CTL逃逸突变的影响 病毒式健身。这些研究将为早期进化的贡献提供重要的新信息 HIV对免疫调控和发病机制的影响。我们会： 1.识别CDS T细胞表位内快速进化和传递的突变，并确定其 对CD8+T细胞反应的正常免疫优势模式的影响。 2.确定急性艾滋病毒-1感染后迅速恢复的残留物，以及传播的残留物的影响 免疫优势CDS表位内的突变对病毒适合性的影响。 3.确定传播的HIV-1毒株的病毒适合性及其对早期遏制艾滋病的贡献 爱滋病毒。

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.