Genetic Risk of HIV Acquisition: Mechanisms of Resilience

项目总结/摘要 这份新的R21提交文件的标题是"艾滋病毒获得的遗传风险：复原力的机制"。后不久 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，随后在人群中得到证实 在海地和非洲发现了HIV-1感染者。除了通过性行为、静脉注射 使用受污染的血液制品或药物可能导致感染，以及母亲对孩子的感染。 传输血液感染被确定为最高风险，有不同的性接触途径 与不同的可识别的感染风险相关。在抗逆转录病毒药物疗法出现之前， 受感染母亲所生婴儿中约三分之一受感染，三分之二未受感染。因此，看来 流行病学和行为因素可以预测HIV-1易感性。然而，暴露于 未感染的HIV感染者帮助鉴定了CCR5受体的Δ 32缺陷型， 在CD4+细胞的表面错误折叠，不能被感染，并以纯合子形式，导致对 使用病毒感染R5。然而，没有发现全基因组显著的多态性与 与HIV-1的获得，这导致该领域远离遗传关联分析。我们很困惑 最近的研究表明，性工作者暴露于HIV-1，尽管有高危行为， 并想知道是否已经错过了对HIV-1感染的遗传弹性。群体遗传学方法 近年来得到了长足的发展，现在甚至在 中等规模的基因广泛关联研究（GWAS）。在初步数据中，我们重新分析了最大的GWAS， 并使用基因水平富集分析和多基因风险评分来识别新基因 以及与获得风险相关的炎症标志物。我们已经证明，HIV-1的获得是一个令人惊讶的 遗传性状，某些细胞因子与HIV-1的恢复力有关。这些发现可能导致 预防HIV-1感染的潜在新方法，包括针对高危人群的干预措施。在这 授予，我们将扩大我们的遗传学的分析，获得验证队列，包括非欧洲 祖先和确定免疫恢复机制。更好地了解生物因素 影响艾滋病病毒感染有可能发展我们对艾滋病病毒感染的基本理解， 预防战略和减少社会耻辱。

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.