Host Genetic Determinants of HIV Pathogenesis

描述（由申请人提供）：越来越多的证据表明，个体的宿主基因构成是HIV/AIDS易感性的重要决定因素。我们整合了遗传学、免疫学和进化，并将它们作为强大的工具来(a)揭示影响HIV-1体内发病机制的复杂宿主基因-基因相互作用；(b)确定这些决定因素在人口一级对艾滋病毒-1流行病的相对影响；(c)将这些发现转化为现实生活中的实际问题，例如通过基于基因的艾滋病预测改善患者的临床护理，以及设计和评价疫苗试验；(d)阐明体内保护性抗艾滋病毒反应的免疫相关因素，可以为合理的疫苗设计建模。在当前的应用中，我们将测试总体假设：(1)CD4 - CD4配体- CCR5 - CCR5配体关系成员的表达，包括辅助受体信号的相关转导，将改变HIV/AIDS的易感性（目标#1）；（II）影响T细胞动力学和调控的候选基因的表达将改变艾滋病毒/艾滋病的易感性（目标#2）；（三）艾滋病毒/艾滋病的易感性与α -防御素的基因剂量有关（目的#3）。在目标#4中，我们将探索将宿主遗传学置于更广泛框架中的方法，并将确定它们对艾滋病预测、T细胞动力学和该流行病的其他公共卫生方面的影响。因此，本提案寻求资金支持一项合作研究，通过整合两个不同研究团队的独特技能和资源，即遗传学（UTHSCSA），流行病学/病毒学/统计学（WHMC），群体遗传学（犹他）和免疫学/病毒学（范德比尔特），探索HIV/AIDS易感性的遗传机制。这项研究将利用已有的、匿名的、没有关联的人类样本。IRB先前已根据45 CFR 46.110授权的快速审查获得了对这些标本进行遗传研究的批准，并且是现有已批准的IRB提案的延续。

DESCRIPTION (provided by applicant): 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 genetic-based 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.