Investigating the genetic basis of CD4-intrinsic HIV control

描述(申请人提供)：除非接受HAART治疗，否则大多数HIV感染者最终将经历病毒载量增加和CD4T细胞减少，从而导致艾滋病。然而，大约1/200-1/500的人能够在没有治疗的情况下自然控制病毒，保持正常的CD4T细胞水平，并无限期地抵抗向艾滋病的进展。这些精英控制器(EC)一直是人们深入研究的对象。我们通过与范德比尔特大学的研究人员合作，从当地耶鲁/退伍军人管理局社区收集了21名ECS。在一项初步研究中，我们发现来自几个ECs的CD4T细胞对体外M嗜单周期HIV感染具有抵抗力。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个罕见的基因变异，包括单核苷酸多态和插入/缺失。然而，事实证明，识别这些变体中哪些有助于精英控制的任务具有挑战性。在这项研究中，我们将全面描述我们在几种内皮细胞的CD4T细胞中观察到的对HIV感染的抵抗力。我们将利用家族性研究的力量来检查这种表型是否有可遗传的成分。然后，我们将进行外显子组测序，以确定与这种表型相关的罕见基因变体。我们还将进行转录组分析，以确定与这种表型相关的基因表达模式。

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. We will also perform transcriptome analysis, to identify gene expression patterns that are associated with this phenotype.