Host Genetic Control of HIV

HIV的宿主基因控制

• 批准号: 9066609
• 负责人: Richard Sutton
• 金额: $ 73.86万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9066609
• 关键词: Alcohol or Other Drugs use; Amino Acids; Antiviral Agents; Binding; CD4 Positive T Lymphocytes; Candidate Disease Gene; Cell Count; Cells; Chinese People; Collaborations; DNA; DNA Sequence Alteration; Ethiopian; Family Study; Genes; Genetic; Genomic DNA; HIV; HIV Infections; HLA-B Antigens; Health; Immunologic Deficiency Syndromes; In Vitro; Individual; Inheritance Patterns; Modeling; Mutation; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Phenotype; Research Personnel; Resistance; Risk Factors; T-Cell Depletion; Testing; Vaccines; Veterans; Virus; Virus Replication; cohort; exome sequencing; genome wide association study; man; patient population

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）：对于大多数受感染的个体，HIV无可避免地导致CD4+ T细胞耗竭和深远的免疫缺陷。幸运的是，很少有HIV感染会导致病毒复制极为有限，并且维持周围CD4+ T细胞计数。这些被称为“精英控制者”的患者一直接受深入研究，因为了解他们如何控制病毒应为疫苗的努力提供信息。大量EC的GWA鉴定出与EC表型相关的HLA-B肽结合袋中的几种非同义氨基酸的变化。然而，这些突变仅造成约20％的观察到效应，并且有人提出，即使较大的GWA也不会发现稀有的“私人”突变，即大多数EC表型。我希望确定那些可能导致EC中精美控制O HIV的罕见遗传突变。为此，我提出了来自EC的基因组DNA的整个外显子组测序（WES）。我们的小组完成了约24个EC的WES，并且已经有几个有前途的基因铅。现在，我们希望将外显子测序扩展到美国和世界各地的数十个EC。患者群体包括埃塞俄比亚人（与亚的斯亚贝巴和马卡尔的调查员合作），西班牙人（来自大量的EC，是药物使用者），中国人和美国退伍军人（其中许多人将其用作HIV习得风险因素）。从WES鉴定出的候选基因将进行体外功能研究。重要的是，我们已经确定了具有对艾滋病毒的细胞内抗性的EC的子集。这些EC将使我们能够以家庭研究为重点探索精英控制的遗传学，以确定遗传模式和因果基因。最后，我希望能确定负责HIV宿主控制的遗传因素。