Host Genetic Determinants of HIV Pathogenesis

越来越多的证据表明，一个人的宿主基因构成是一个强烈的决定因素 艾滋病毒/艾滋病易感性。我们整合了遗传学、免疫学和进化论，并将它们用作 强大的工具，以(A)揭示复杂的宿主基因-基因相互作用，在体内影响艾滋病毒-1的发病机制； (B)在人口一级确定这些决定因素对艾滋病毒-1流行的相对贡献； 将这些发现转化为现实生活中的实际问题，如通过基于基因的方法改善患者的临床护理 艾滋病的预测以及疫苗试验的设计和评价；和(D)阐明 体内保护性抗HIV反应的免疫相关性可以为合理的疫苗设计建模。 在当前的应用中，我们将检验总体假设：(I)CD4-CD4成员的表达 配体-CCR5-CCR5配体关系，包括相关的辅受体信号转导，将改变 艾滋病毒/艾滋病易感性(目标1)；(2)影响T细胞动力学和 管制将改变艾滋病毒/艾滋病的易感性(目标2)；和(3)艾滋病毒/艾滋病的易感性与基因有关 剂量α-防御素(目标3)。在目标4中，我们将探索将宿主遗传学置于更广泛的 框架，并将确定其对艾滋病预测、T细胞动力学和其他公众的影响 这一流行病的健康方面。因此，这项提案寻求资金支持一项合作研究，以探讨 通过融合独特的技能和资源来研究艾滋病毒/艾滋病易感性的遗传机制 两个不同的研究小组，即遗传学(UTHSCSA)、流行病学/病毒学/统计学(WHMC)、 群体遗传学(犹他州)和免疫学/病毒学(范德比尔特)。这项研究将利用预先存在的， 匿名的、没有关联的人类标本。IRB已批准对这些标本进行遗传研究 以前在45 CFR 46.110授权的快速审查下获得，是 现有的已获批准的内部审查委员会建议。

There is growing evidence that the host genetic make-up of an individual is a strong determinant of HIV/AIDS susceptibility. We have integrated genetics, immunology, and evolution, and used them as powerful tools to (a) uncover complex host gene-gene interactions that influence HIV-1 pathogenesis in vivo; (b) determine the relative contribution to these determinants to the HIV-1 epidemic at the population level; (c) translate these findings to real life practical issues such as improved clinical care of patients via geneticbased prognostication of AIDS as well as design and evaluation of vaccine trials; and (d) shed light on the immune correlates of a protective anti-HIV response in vivo that can be modeled for rational vaccine design. In the current application we will test the overall hypothesis that (I) expression of members of the CD4 - CD4 ligand - CCR5 - CCR5 ligand nexus, including relevant transducers of coreceptor signals, will alter HIV/AIDS susceptibility (aim #1); (II) expression of candidate genes that influence T cell dynamics and regulation will alter HIV/AIDS susceptibility (aim #2); and (III) HIV/AIDS susceptibility is linked to the gene dose of alpha-defensins (aim #3). In aim #4, we will explore means to place host genetics in a broader framework, and will determine their influence on AIDS prognostication, T cell dynamics and other public health aspects of the epidemic. Thus, this proposal seeks funds to support a collaborative study to explore the genetic mechanisms underlying HIV/AIDS susceptibility by amalgamating the unique skills and resources of two different research teams, namely genetics (UTHSCSA), epidemiology/virology/statistics (WHMC), population genetics (Utah) and immunolog/virology (Vanderbilt). This study will utilize pre-existing, anonymous, unlinked human specimens. IRB approval for genetic study of these specimens has been previously obtained under expedited review authorized by 45 CFR 46.110, and is a continuation of an existing approved IRB proposal.