Host Genetic Control of HIV

HIV的宿主基因控制

基本信息

批准号：
9271947
负责人：
Richard Sutton
金额：
$ 74.61万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-15 至 2018-11-30
项目状态：
已结题

项目摘要

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.

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 细胞耗竭和严重的免疫缺陷。对于少数幸运者来说，HIV 感染会导致病毒复制极其有限，并且外周 CD4+ 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。 EC 的大量 GWAS 鉴定了 HLA-B 肽结合袋中与 EC 表型相关的几个非同义氨基酸变化。然而，这些突变仅造成约 20% 的观察到的效应，并且有人认为，即使是更大的 GWAS 也无法发现的更罕见的“私人”突变才是大多数 EC 表型的原因。我希望找出那些可能有助于精确控制 EC 中 HIV 的罕见基因突变。为此，我建议对 EC 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前途的基因先导；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。患者群体包括埃塞俄比亚人（与亚的斯亚贝巴和马克莱的研究人员合作）、西班牙人（来自大量吸毒者）、中国和美国退伍军人（其中许多人将吸毒作为感染艾滋病毒的风险因素）。从 WES 中鉴定出的候选基因将进行体外功能研究。重要的是，我们已经确定了对 HIV 具有细胞内在抵抗力的 EC 子集。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，我希望能够找到负责宿主控制艾滋病毒的遗传因素。