Genetic Risk of HIV Acquisition: Mechanisms of Resilience

感染艾滋病毒的遗传风险：恢复机制

• 批准号: 10077116
• 负责人: DOUGLAS F NIXON
• 金额: $ 25.43万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10077116
• 关键词: Adoption; Affect; African; Anti-Retroviral Agents; Applications Grants; Behavioral; Binding; Biological; Biological Factors; CCR5 gene; CD4 Positive T Lymphocytes; Cells; Code; Color; Communities; Complex; Comprehension; Country; Data; Developed Countries; Disease; Distal; Drug usage; Environmental Exposure; Epidemic; Epidemiology; Exposure to; Gays; Gene Frequency; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Genetic Transcription; Genetic study; Glean; Grant; HIV; HIV Infections; HIV-1; Haiti; Hematologic Agents; Heritability; Homozygote; Immune system; Immunologics; In Vitro; Individual; Infection; Intervention; Lead; Lesbian Gay Bisexual Transgender Queer; Los Angeles; Mammalian Cell; Mediating; Methods; Modernization; Mothers; Mutation; New York; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Play; Population; Population Genetics; Predisposition; Prevention; Prevention strategy; Proteins; Resistance to infection; Risk; Risk Factors; Role; Route; Sepsis; Sexually Transmitted Diseases; Surface; Testing; Unsafe Sex; Validation; Vertical Disease Transmission; Viral; Virus; Work; base; blood product; case control; causal variant; cell type; cohort; condoms; cytokine; drug abstinence; genetic analysis; genetic association; genetic variant; genome wide association study; genome-wide; high risk; high risk behavior; high risk population; improved; infection risk; inflammatory marker; intravenous administration; intravenous drug use; men; novel; polygenic risk score; pre-exposure prophylaxis; premature; prevent; receptor; resilience; risk variant; sex; social stigma; statistics; trait

PROJECT SUMMARY/ABSTRACT This new R21 submission is entitled “Genetic Risk of HIV Acquisition: Mechanisms of Resilience”. Soon after the identification of a new disease amongst gay men in Los Angeles and New York, originally called GRID, epidemiological evidence suggested a sexually transmitted infection, which was then confirmed in populations in Haiti and African identified with infection with HIV-1. In addition to infection through sex, intravenous administration of contaminated blood products or drug use could lead to infection, as well as mother to child transmission. Blood infection was identified as the highest risk, with different routes of sexual exposure associated with different identifiable risks of infection. Before antiretroviral drug therapy became available, around one third of babies born to infected mothers were infected, while two thirds were not. Thus, it appeared that epidemiological and behavioral factors could predict HIV-1 susceptibility. However, individuals exposed to HIV infection who had not became infected helped identify the defective Δ32 form of CCR5 receptor which misfolded at the surface of a CD4+ cell and could not be infected, and in homozygote form, led to resistance to infection with R5 using viruses. However, no genome-wide significant polymorphisms were found associated with HIV-1 acquisition, which has led the field to move away from genetic association analyses. We were puzzled from recent studies of sex workers exposed to HIV-1 who did not become infected despite high risk behavior and wondered if genetic resilience to HIV-1 acquisition had been missed. Population genetic methods have developed substantially in recent years, now allowing for powerful, biologically-informative analyses even in moderately-sized gene wide association studies (GWAS). In preliminary data, we reanalyzed the largest GWAS of HIV-1 acquisition and used gene-level enrichment analyses and polygenic risk scoring to identify novel genes and inflammatory markers associated with acquisition risk. We have shown that HIV-1 acquisition is a surprisingly heritable trait, and that certain cytokines are associated with HIV-1 resilience. These findings could lead to potential new ways of preventing HIV-1 infection, including targeted interventions to those at highest risk. In this grant, we will extend our analyses of the genetics of acquisition to validation cohorts including non-European ancestry and determine mechanisms of immunological resilience. A better understanding of biological factors influencing acquisition has the potential to develop our basic comprehension of HIV-1 acquisition, improve prevention strategies and reduce social stigma.

项目摘要/摘要 这种新的R21提交的标题为“艾滋病毒获取的遗传风险：弹性机制”。不久 在洛杉矶和纽约的男同性恋者中鉴定出一种新疾病，最初称为Grid， 流行病学证据表明性传播感染，然后在人群中得到证实 在海地和非洲人，患有HIV-1感染。除了通过性感染，静脉注射 受污染的血液产品或吸毒的施用可能导致感染，以及母亲对儿童 传播。血液感染被确定为最高风险，有不同的性暴露途径 与不同的感染风险相关。在可用抗逆转录病毒药物治疗之前 受感染母亲出生的婴儿中约有三分之一被感染，而三分之二则没有。那看了 流行病学和行为因素可以预测HIV-1易感性。但是，个人暴露于 尚未感染的HIV感染有助于确定CCR5受体的缺陷Δ32形式 在CD4+细胞的表面错误折叠，无法感染，并以纯合形式导致了对 使用病毒感染R5。但是，未发现全基因组的重要多态性 随着HIV-1的采集，这导致该领域摆脱了遗传关联分析。我们很困惑 从最近暴露于没有被感染的高风险行为的性工作者的研究中 并想知道是否错过了对HIV-1获取的遗传弹性。人口遗传学方法具有 近年来开发的基本开发，现在允许进行强大的生物信息分析 中等大小的基因范围研究（GWAS）。在初步数据中，我们重新分析了最大的GWA HIV-1采集并使用基因级富集分析和多基因风险评分来鉴定新基因 和与采集风险相关的炎症标记。我们已经表明，HIV-1的获取是一个令人惊讶的 可遗传的特征，某些细胞因子与HIV-1弹性有关。这些发现可能导致 预防HIV-1感染的潜在新方法，包括针对风险最高的人的有针对性干预措施。在这个 Grant，我们将将获取遗传学的分析扩展到包括非欧洲的验证群体 祖先并确定免疫弹性的机制。更好地理解生物因素 影响收购有可能发展我们对HIV-1获取的基本理解，改善 预防策略并减少社会污名。