Host genetic determinants of HIV-AIDS susceptibility in a VA cohort

描述(由申请人提供)： 越来越多的证据表明，在未经治疗的艾滋病毒感染和高效抗逆转录病毒治疗(HAART)期间，宿主的遗传构成是艾滋病毒/艾滋病易感性的重要决定因素。我们将使用最先进的强大的遗传和统计工具以及有针对性的候选基因方法来确定在退伍军人管理局进行高效抗逆转录病毒治疗(HAART)期间影响艾滋病毒/艾滋病易感性和免疫恢复的遗传因素，即退伍军人退伍军人年龄队列研究(VAS)。因此，这些研究将(A)揭示在体内HAART期间影响HIV-1致病和免疫恢复的复杂宿主基因-基因相互作用；(B)在人群水平上确定这些决定因素对HIV-1流行的相对贡献；(C)将这些研究结果转化为现实生活中的实际问题，例如通过基于遗传的艾滋病预测以及HAART期间的免疫恢复来改善对患者的临床护理；以及(D)酒精和年龄在免疫耗竭/恢复中的影响。在目前的应用中，我们将检验以下总体假设：(I)在HAART中，CD4-CD4配体-CCR5-CCR5配体网络成员的表达，包括相关的辅受体信号转导，将改变HIV/AIDS的易感性和免疫恢复(目标1)；(Ii)影响先天和获得性免疫反应的选定候选基因的表达和相互作用将改变HAART中的艾滋病毒/艾滋病易感性和免疫恢复(目标2)。这些基因包括：(I)MHC和KIR基因；(Ii)编码细胞内在因子(TRIM5和APOBEC3家族)的基因；(Iii)参与HIV生命周期的基因，如PPIA和TSG101；(Iv)被鉴定为HIV依赖因子(HDF)；以及(Iv)17q12上富含趋化因子基因的拷贝数变异(CNV)、补体成分(C4a和C4b)、Fc受体(FCGR3)和防御素。因此，这项提案寻求批准使用退伍军人事务部中央生物储存库的标本来支持一项合作研究，通过合并德克萨斯州圣安东尼奥的退伍军人事务部艾滋病和艾滋病毒感染研究中心(PI：Dr Ahuja)和康涅狄格州纽黑文耶鲁大学医学院(PI：Dr Justice)的独特技能和资源，探索HAART期间艾滋病毒/艾滋病易感性和免疫恢复的遗传机制。 公共卫生相关性： 拟议的研究将为影响艾滋病毒和艾滋病易感性的宿主因素提供新的见解，这些发现可能为开发疗法和疫苗提供新的途径。

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 during untreated HIV infection and immune recovery during highly active antiretroviral therapy (HAART). We will use state-of-the-art powerful genetic and statistical tools and targeted candidate gene approaches to identify genetic factors that influence HIV-AIDS susceptibility as well as immune recovery during highly active antiretroviral therapy (HAART) in a large cohort of adults from the VA, namely VA Aging Cohort Study (VACS). These studies will thus (a) uncover complex host gene-gene interactions that influence HIV-1 pathogenesis and immune recovery during HAART 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 immune recovery during HAART; and (d) the influence of alcohol and age in immune depletion/recovery. 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 and immune recovery during HAART (aim #1); (II) expression of and interaction between selected candidate genes that influence innate and adaptive immune responses will alter HIV-AIDS susceptibility and immune recovery during HAART (aim #2). These include genes (i) at the MHC and KIR locus; (ii) encoding cellular intrinsic factors (TRIM5 and Apobec3 family); (iii) involved in the HIV life cycle such as PPIA and TSG101; (iv) identified as HIV dependency factors (HDF), and (iv) Copy Number Variation (CNV) at the chemokine gene-rich locus on chromosome 17q12, complement components (C4A and C4B), Fc receptors (FCGR3), and defensins. Thus, this proposal seeks approval for the use of specimens at VA Central biorepository to support a collaborative study to explore the genetic mechanisms underlying HIV/AIDS susceptibility and immune recovery during HAART by amalgamating the unique skills and resources of the research teams at the VA Center for AIDS and HIV Infection at San Antonio, TX (PI: Dr Ahuja) and Yale University School of Medicine, New Haven, CT (PI: Dr Justice). PUBLIC HEALTH RELEVANCE: The studies proposed will provide new insights into the host factors that influence susceptibility to HIV and AIDS, and these findings could provide new ways to develop therapies and vaccines.