Investigating the genetic basis of CD4-intrinsic HIV control

描述（由申请人提供）：大多数hiv感染者最终会经历病毒载量增加和CD4+T细胞下降，导致艾滋病，除非给予HAART治疗。然而，约有1/200-1/500人能够在没有治疗的情况下自然地控制病毒，保持正常的CD4+ T细胞水平，并无限期地抵抗艾滋病的进展。这些精英控制者（ec）一直是深入研究的主题。通过与范德比尔特大学（Vanderbilt University）的研究人员的合作，我们从当地的耶鲁/弗吉尼亚社区收集了21名ec。在初步研究中，我们发现来自几种内皮细胞的CD4+ T细胞在体外对嗜m型单周期HIV感染具有抗性。我们还对这些个体进行了外显子组测序（即基因组内所有编码序列的测序），并鉴定了大约300种罕见的基因变异，包括单核苷酸多态性和插入/缺失。然而，确定这些变异中哪些有助于精英控制的任务被证明是具有挑战性的。在这项研究中，我们将全面表征我们在几种内皮细胞的CD4+ T细胞中观察到的对HIV感染的抵抗力。我们将利用家族研究的力量来检查这种表型是否有遗传成分。然后，我们将执行外显子组测序，以确定与该表型相关的罕见基因变异。

DESCRIPTION (provided by applicant): The majority of HIV-infected individuals will eventually experience an increase in viral load and a decline in CD4+T cells, leading to AIDS, unless HAART is administered. However, ~1/200-1/500 individuals are able to naturally control the virus in the absence of therapy, retaining normal CD4+ T cell levels and resisting progression to AIDS indefinitely. These elite controllers (ECs) have been the subject of intensive study. We have collected a cohort of 21 ECs from the local Yale/VA community and through collaborative efforts with investigators at Vanderbilt University. In a preliminary study, we found that CD4+ T cells from several ECs were resistant to M-tropic single cycle HIV infection ex vivo. We also performed exome sequencing on these individuals (i.e. sequencing of all the coding sequences within the genome) and identified approximately 300 rare gene variants, including single nucleotide polymorphisms and insertions/ deletions. However, the task of identifying which of these variants contribute to elite control has proved challenging. In this study we will comprehensively characterize the resistance to HIV infection that we observed in the CD4+ T cells of several ECs. We will harness the power of a familial study to examine if there is a heritable component to this phenotype. We will then perform exome sequencing to identify rare gene variants that are associated with this phenotype.