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 这份新的R21意见书题为“艾滋病毒感染的遗传风险：复原力机制”。不久之后 在洛杉矶和纽约的男同性恋者中发现了一种新的疾病，最初被称为GRID， 流行病学证据表明是性传播感染，随后在人群中得到确认 在海地和非洲，被确认感染了艾滋病毒-1。除了通过性行为感染外，静脉注射 服用受污染的血液产品或使用药物可能会导致感染以及母婴传播。 变速箱。血液感染被确定为最高风险，有不同的性接触途径 与不同可识别的感染风险相关。在抗逆转录病毒药物治疗出现之前， 在受感染母亲所生的婴儿中，约有三分之一受到感染，而三分之二没有。因此，它看起来 流行病学和行为因素可以预测HIV-1的易感性。然而，暴露于 未感染艾滋病毒的人帮助确定了CCR5受体Δ32型缺陷，该受体 在CD4+细胞表面错误折叠，不能被感染，并以纯合子形式，导致对 使用病毒感染R5病毒。然而，没有发现与全基因组显著的多态相关的 随着HIV-1病毒的获得，导致该领域不再进行遗传关联分析。我们大惑不解 最近对暴露于HIV-1的性工作者的研究表明，尽管有高危行为，但他们没有被感染 并想知道是否错过了对HIV-1感染的遗传弹性。种群遗传学方法有 近年来有了很大的发展，现在甚至可以进行强大的生物信息学分析 中等规模的全基因关联研究(GWAS)。在初步数据中，我们重新分析了最大的 并使用基因水平浓缩分析和多基因风险评分来识别新基因 以及与收购风险相关的炎性标志物。我们已经表明，HIV-1的感染是一个令人惊讶的 可遗传的特征，以及某些细胞因子与艾滋病毒-1的复原力有关。这些发现可能会导致 预防艾滋病毒-1感染的潜在新方法，包括对高危人群进行有针对性的干预。在这 Grant，我们将把我们对习得遗传学的分析扩展到包括非欧洲人在内的验证队列 血统和确定免疫弹性的机制。更好地了解生物因素 影响获得有可能发展我们对HIV-1获得的基本理解，提高 预防战略和减少社会污名。