Investigating the genetic basis of CD4-intrinsic HIV control

描述（由申请人提供）：除非给予HAART，否则大多数HIV感染者最终将经历病毒载量增加和CD 4 +T细胞下降，导致AIDS。然而，约1/200-1/500的个体能够在没有治疗的情况下自然控制病毒，保持正常的CD 4 + T细胞水平并无限期地抵抗进展为艾滋病。这些精英控制器（EC）一直是深入研究的主题。 我们从当地的耶鲁/弗吉尼亚社区收集了21个EC，并通过与范德比尔特大学的研究人员的合作努力。在一项初步研究中，我们发现，CD 4 + T细胞从几个EC是抗M嗜性单周期HIV感染离体。我们还对这些个体进行了外显子组测序（即对基因组内的所有编码序列进行测序），并确定了大约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，确定这些变体中哪些有助于精英控制的任务已被证明具有挑战性。 在这项研究中，我们将全面表征我们在几个EC的CD 4 + 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，我们将进行外显子组测序，以确定与这种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.