Host Genetic Determinants of HIV Pathogenesis

越来越多的证据表明，个体的宿主遗传构成是一个强有力的决定因素， 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， （a）揭示影响体内HIV-1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流行病的相对贡献;（c） 将这些发现转化为真实的生活中的实际问题，例如通过基于遗传学的方法改善患者的临床护理， 艾滋病的统计以及疫苗试验的设计和评价;以及（d）阐明 免疫相关的体内保护性抗HIV反应，可以为合理的疫苗设计建模。 在本申请中，我们将测试以下总体假设：（I）CD 4-CD 4-T细胞的成员的表达， 配体-CCR 5-CCR 5配体关系，包括辅助受体信号的相关转导物，将改变 艾滋病毒/艾滋病易感性（目标1）;（二）影响T细胞动力学的候选基因的表达， 调控将改变艾滋病毒/艾滋病易感性（目标#2）;（III）艾滋病毒/艾滋病易感性与基因有关 剂量的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环境中的方法。 框架，并将确定其对艾滋病预后、T细胞动力学和其他公众的影响 流行病的健康方面。因此，本提案寻求资金，以支持一项合作研究， 通过融合独特的技能和资源， 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）。这项研究将利用现有的， 匿名无关联的人类标本IRB已批准对这些标本进行遗传学研究， 先前根据45 CFR 46.110授权的快速审查获得，并且是 已批准的IRB提案。

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.