Host Genetic Control of HIV

描述（由申请人提供）：对于大多数感染者来说，HIV不可避免地导致CD4+ T细胞耗竭和深度免疫缺陷。对于少数幸运的HIV感染，病毒复制极其有限，外周血CD4+ T细胞计数得以维持。这些被称为“精英控制者”的患者受到了深入研究，因为了解他们如何控制病毒应该为疫苗工作提供信息。大量EC的GWAS鉴定出HLA-B肽结合口袋中与EC表型相关的几个非同义氨基酸变化。然而，这些突变仅占观察到的效应的约20%，并且有人认为，即使是更大的GWAS也不会发现的更罕见的“私有”突变是大多数EC表型的原因。我希望找出那些罕见的基因突变，它们可能有助于在ec中精确地控制艾滋病毒。为此，我建议对ec的基因组DNA进行全外显子组测序（WES）。我们小组已经完成了约24个ECs的WES，并已经有了几个有希望的基因引线；我们现在希望将外显子组测序扩展到美国和世界各地的数十个其他ec。患者人群包括埃塞俄比亚人（与亚的斯亚贝巴和马克莱的研究人员合作），西班牙人（来自大量药物使用者的ECs），中国人和美国退伍军人（其中许多人将药物使用作为其感染艾滋病毒的风险因素）。从WES中鉴定的候选基因将进行体外功能研究。重要的是，我们已经确定了一个对HIV具有细胞内在抗性的ECs子集。这些ec将使我们能够探索精英控制的遗传学，以家庭研究为重点，以确定遗传模式和致病基因。最后，我希望能够确定宿主控制HIV的遗传因素。

DESCRIPTION (provided by applicant): For most infected individuals, HIV leads inexorably to CD4+ T cell depletion and profound immunodeficiency. For a fortunate few HIV infection results in extremely limited viral replication and peripheral CD4+ T cell counts are maintained. These patients, termed 'Elite Controllers', have been subject to intensive study since understanding how they control the virus should inform the vaccine effort. A large GWAS of ECs identified several non-synonymous amino acid changes in the peptide binding pocket of HLA-B that are associated with the EC phenotype. Those mutations, however, were only responsible for ~20% of the observed effect, and it has been suggested that much rarer, 'private' mutations that would not be uncovered by even a larger GWAS are responsible for the majority of the EC phenotype. I wish to identify those rare genetic mutations that may be contributing to the exquisite control o HIV in ECs. To do so, I propose whole exome sequencing (WES) of genomic DNA from ECs. Our group has completed WES of ~24 ECs and already has several promising gene leads; we now wish to expand exome sequencing to dozens of other ECs throughout the U.S. and world. Patient populations include Ethiopians (in collaboration with investigators in Addis Ababa and Makele), Spaniards (from a large cohort of ECs that are substance users), Chinese, and U.S. Veterans (many of whom have substance use as their HIV acquisition risk factor). Candidate genes identified from WES will be subjected to in vitro functional studies. Importantly, we have identified a subset of ECs who have cell-intrinsic resistance to HIV. Those ECs will allow us to explore the genetics of elite control, with a focus on family studies, in order to determine inheritance patterns and causative genes. In the end I hope to have identified genetic factors responsible for host control of HIV.