The impact of CD8 T cells on viral control and evolution in HIV-infected infants

描述（由申请人提供）：在HIV感染的成人中，特定I类HLA分子的表达与增强的控制HIV的能力相关，这在感染的最早阶段是明显的，而其他等位基因与快速进展为AIDS相关。这些数据表明CDS T细胞应答在建立病毒遏制中的重要作用。尽管已经进行了广泛的研究来表征成人中CDS T细胞对HIV的应答，但HLA的关键影响的潜在机制仍然不清楚。母婴传播艾滋病毒提供了几个优势，作为一个模型，在其中定义的免疫相关的病毒控制在急性感染，和病毒逃逸突变对遏制艾滋病毒的影响。垂直感染是一个可预测的事件，使前瞻性研究的婴儿T细胞反应从感染的最早阶段。此外，对单倍相合的母婴对的研究允许比较在由共享和非共享HLA等位基因限制的表位内传播的母体逃逸突变的后果。虽然在婴儿早期包含HIV病毒血症的能力是一个强有力的预测生存，很少有信息是关于抗原表位特异性和功能特征的HIV特异性T细胞在婴儿。所提出的研究的总体目标是确定CDS介导的免疫控制的相关性，或缺乏免疫控制，以下HIV的垂直传播。我们将描述CDS T细胞反应与围产期早期HIV感染期间病毒复制的成功和不成功限制相关，重点关注与进化枝B感染的缓慢和快速进展相关的等位基因。目前基于多参数流式细胞术的方法将使我们能够以前所未有的细节解剖婴儿的病毒特异性T细胞反应，因为它们允许使用非常小的样本同时评估多种T细胞功能。此外，我们将确定CDS T细胞反应在急性围产期感染期间选择病毒逃逸突变的程度，并评估这些突变对婴儿控制病毒血症能力的影响。最后，我们将研究传播的母体逃逸突变对CDS反应和垂直感染婴儿的病毒遏制的影响。确定母亲逃逸突变在垂直传播后恢复的频率可以提供一种方法来估计CDS逃逸对人群水平病毒进化的可能影响。此外，在传播后迅速恢复为野生型的表位代表了有吸引力的疫苗靶标，因为它们能够诱导适应性减弱病毒突变，以及随着病毒进化它们将继续在群体中繁殖的可能性。

DESCRIPTION (provided by applicant): In HIV-infected adults, expression of particular class I HLA molecules is associated with an enhanced ability to control HIV that is evident during the earliest stages of infection, while other alleles are associated with rapid progression to AIDS. These data suggest an important role for the CDS T cell response in establishing viral containment. Although extensive studies have been performed to characterize the CDS T cell response to HIV in adults, the mechanism underlying the critical influence of HLA remains unclear. Mother-to-child transmission of HIV affords several advantages as a model in which to define the immune correlates of viral control during acute infection, and the impact of viral escape mutations on containment of HIV. Vertical infection is a predictable event, enabling prospective study of the infant T cell response from the earliest stages of infection. Moreover study of haploidentical mother-infant pairs permits comparison of the consequences of transmitted maternal escape mutations within epitopes restricted by shared and unshared HLA alleles. Although the ability to contain HIV viremia during early infancy is a strong predictor of survival, little information is available regarding the epitope specificity and functional characteristics of HIV-specific T cells in infants. The overall aim of the proposed studies is to define the correlates of CDS mediated immune control, or lack thereof, following vertical transmission of HIV. We will characterize the CDS T cell responses associated with successful and unsuccessful restriction of viral replication during early perinatal HIV infection, focusing on alleles that are associated with slow and rapid progression in clade B infection. Current methods based on multiparameter flow cytometry will allow us to dissect virus-specific T cell responses of infants in unprecedented detail, as they permit simultaneous assessment of multiple T cell functions using very small samples. In addition, we will determine the extent to which CDS T cell responses select for viral escape mutations during acute perinatal infection, and assess the impact of these mutations on the ability of infants to control viremia. Finally, we will examine the impact of transmitted maternal escape mutations on the CDS response and viral containment in the vertically infected infant. Determination of the frequency with which maternal escape mutations revert following vertical transmission could provide a means to estimate the probable impact of CDS escape on viral evolution at the population level. Moreover, epitopes that rapidly revert to wild-type following transmission represent attractive vaccine targets due to their ability to induce fitness-attenuating viral mutations, as well as the likelihood that they will continue to propagate in the population as the virus evolves.