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

描述(申请人提供)：在感染艾滋病毒的成年人中，特定的I类人类白细胞抗原分子的表达与增强的控制艾滋病毒的能力有关，这在感染的最早阶段是明显的，而其他等位基因与快速发展为艾滋病有关。这些数据表明CDS T细胞反应在建立病毒遏制中起着重要作用。虽然已经进行了广泛的研究来表征成人CDS T细胞对HIV的反应，但其关键影响机制仍不清楚。作为确定急性感染期间病毒控制的免疫相关性以及病毒逃逸突变对遏制艾滋病毒的影响的模型，艾滋病毒母婴传播提供了几个优点。垂直感染是一种可预见的事件，能够从感染的最早阶段对婴儿T细胞反应进行前瞻性研究。此外，对单倍体相合的母婴对的研究允许比较在受共享和非共享的HLA等位基因限制的表位内传播的母体逃逸突变的后果。尽管在婴儿早期控制HIV病毒血症的能力是一个强有力的生存预测因素，但关于婴儿中HIV特异性T细胞的表位特异性和功能特征的信息很少。拟议研究的总体目标是确定在HIV垂直传播后CDS介导的免疫控制或缺乏免疫控制的相关性。我们将描述与围产期HIV感染早期病毒复制成功和失败相关的CDS T细胞反应，重点关注与B分支感染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详细程度剖析婴儿的病毒特异性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，我们将确定在急性围产期感染期间CDS T细胞反应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，我们将检查传播的母体逃逸突变对垂直感染婴儿的CDS反应和病毒遏制的影响。确定母体逃逸突变在垂直传播后回复的频率可以提供一种手段，在人群水平上估计CDS逃逸对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着有吸引力的疫苗靶标，因为它们能够诱导适合度减弱的病毒突变，以及随着病毒的进化它们将继续在人群中传播的可能性。

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.