HLA-associated control-lack of control in HIV infection

描述(由申请人提供)：特定的人类白细胞抗原I类与不同的病毒设定点和进展到艾滋病毒疾病的速率相关，为CD8T细胞影响艾滋病毒感染结局的机制提供了潜在的见解。某些等位基因与有效的控制有关，而其他等位基因与快速进展有关。这些研究的基础假设是，这些与人类白细胞抗原相关的HIV结果的多样性可能主要与目标特定表位的差异有关，这反过来又决定了CD8 T细胞反应的有效性。在这笔赠款的最初资助期内，我们将重点放在受疫情严重影响的南非德班进行调查。我们已经确定了与低病毒设定点相关的主要的HLAI类等位基因，以及与高病毒设定点相关的主要等位基因；我们对CD8T细胞反应进行了全面的实证分析，并确定了大多数在这一感染人群中具有特征靶点的表位。对HLAB*57和B*5801这两个等位基因的初步研究表明，这两个等位基因与该队列中病毒设定点最低相关，这可能是导致免疫控制的一个可能机制。拟议的研究在这些发现的基础上进行了扩展，并额外考虑了与高病毒设定点相关的CD8T细胞特异性。这项拟议工作的一个中心假设是，HIV疫苗的目标不应该是产生尽可能多的CD8T细胞反应，而是只诱导某些有效的CD8T细胞特异性。同样重要的是，对免疫控制有积极有害影响的CD8 T细胞反应需要从这种疫苗中省略。拟议研究的具体目的是a)确定与极端结果相关的少数等位基因所针对的表位；b)确定这些表位中哪些与成功或不成功地控制病毒血症有关；以及c)确定这些表位可能的进化命运，从而确定这些表位与疫苗的相关性。

DESCRIPTION (provided by applicant): Particular HLA class I associations with differential viral set-points and rates of progression to HIV disease provide potential insights into the mechanisms by which CD8+ T cells can influence outcome in HIV infection. Certain alleles are associated with effective control, whilst others are linked to rapid progression. The starting hypothesis underlying these proposed studies is that the diversity of these HLA-associated HIV outcomes may be primarily related to differences in the particular epitopes targeted, which in turn dictate the efficacy of the CD8+ T cell response. During the initial funding period of this grant, we focused our investigations in Durban, South Africa, in a region critically affected by the epidemic. We have identified the principal HLA class I alleles associated with low viral set-point, and those associated with high viral set-point; we have undertaken a comprehensive empirical analysis of the CD8+ T cell responses and have defined the majority of the epitopes that are characteristically targeted in this infected population. Initial studies of HLAB* 57 and B*5801, the two alleles most strong associated with low viral set-point in this cohort, indicated a likely contributory mechanism by which immune control may be brought about. The proposed studies expand on these findings and consider additionally the CD8+ T cell specificities that are associated with high viral set-point. A central hypothesis of this proposed work is that the goal of an HIV vaccine should not be to generate as many CD8+ T cell responses as possible, but rather to induce only certain efficacious CD8+ T cell specificities. Equally important, CD8+ T cell responses that have an actively deleterious influence on immune control need to be omitted from such a vaccine. The specific aims of the proposed studies are to a) define the epitopes that are targeted by the few alleles that are associated with extremes of outcome; b) identify which of these epitopes are associated with successful or unsuccessful control of viremia; and, c) to determine what is the likely evolutionary destiny, and therefore vaccine-relevance of these epitopes.