Host Genetic Control of HIV

描述（由申请人提供）：对于大多数感染者，HIV会无情地导致CD 4 + T细胞耗竭和严重的免疫缺陷。对于少数幸运的HIV感染者，病毒复制极其有限，外周血CD 4 + T细胞计数得以维持。这些被称为“精英控制者”的患者一直受到深入研究，因为了解他们如何控制病毒应该为疫苗工作提供信息。一个大的GWAS的EC确定了几个非同义氨基酸的变化与EC表型相关的HLA-B的肽结合口袋。然而，这些突变仅对观察到的效应的约20%负责，并且已经表明，即使是更大的GWAS也不会发现的更罕见的“私人”突变对大多数EC表型负责。我希望能鉴定出那些罕见的基因突变，它们可能有助于在内皮细胞中精确控制HIV。为此，我建议对EC的基因组DNA进行全外显子组测序（WES）。我们的团队已经完成了约24个EC的WES，并且已经有了几个有希望的基因线索;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（与阿迪斯和Makele的研究人员合作）、西班牙人（来自大量物质使用者的EC队列）、中国人和美国退伍军人（其中许多人将物质使用作为其HIV感染风险因素）。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子集的EC谁具有细胞内在的抗艾滋病毒。这些EC将使我们能够探索精英控制的遗传学，重点是家庭研究，以确定遗传模式和致病基因。最后，我希望能够确定负责宿主控制艾滋病毒的遗传因素。

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.