Host Genetic Factors in the HIV Virus Life-Cycle and HIV Disease Progression

描述（由申请人提供）：在没有治疗的情况下，大多数感染HIV-1的人进展为AIDS并最终死亡。然而，该疾病进展的速率和特征存在明显变化，从数月内快速进展到数年无进展。越来越多的宿主遗传因素被发现可以改变HIV疾病的进展。但是，尽管非洲的艾滋病毒负担最大，但这些遗传因素在非洲队列中尚未得到很好的研究。研究已经评估了与HIV细胞进入相关的基因变异（如CCR 5 A32突变）的作用。然而，现在已知宿主基因介导其他HIV生命周期阶段，包括病毒整合、衣壳形成和细胞内运输和出芽。这些“HIV生命周期宿主基因”对HIV疾病进展的影响尚未得到很好的研究，特别是在非洲人群中。我们正处于一个独特的位置-使用标本正在收集的艾滋病毒抑制在非洲的临床试验，以进一步研究在非洲艾滋病毒疾病进展的宿主遗传因素的作用。合作伙伴预防临床试验（合作伙伴研究）的目的是评估生殖器疱疹抑制与阿昔洛韦在减少艾滋病毒传播的效果。为了实现这一目标，正在东非和南部非洲的不同人群中招募3000对艾滋病毒不一致夫妇，其中感染艾滋病毒的伴侣同时感染生殖器疱疹（HSV-2）和CD 4>250个细胞/mm 3。将向感染艾滋病毒的伴侣提供每日无环鸟苷抑制疱疹，并每季度对双方进行随访，持续18-24个月。全血标本在知情同意的情况下储存，用于今后对艾滋病毒疾病的宿主遗传学研究。这项大型研究提供了一个独特的机会，以评估遗传因素修改艾滋病毒疾病在非洲人。在这里，我们建议使用合作伙伴研究的标本，以评估在生命周期阶段，包括细胞进入，核靶向，衣壳形成，细胞贩运和出芽与艾滋病毒相互作用的基因中的宿主多态性。我们的具体目标是：1）确定合作伙伴研究人群中特定遗传变异的频率，并评估HapMap和其他现有公共SNP发现数据库评估不同非洲人群遗传变异的能力。2)将多变量线性回归和其他统计方法应用于特定目标1中收集的遗传数据，以评估这些遗传变异与疾病进展的相关性，如入组时的病毒载量、随访期间的病毒载量变化和达到CD 4 <200个细胞/mm 3的时间。

DESCRIPTION (provided by applicant): In the absence of therapy, most humans infected with HIV-1 progress to AIDS and eventually die. However, there is distinct variation in the rate and characteristics of that disease progression ranging from rapid progression over months to lack of progression for years. Increasingly, host genetic elements have been found to modify HIV disease progression. But these genetic factors have not been well studied in African cohorts despite the fact that the HIV burden is greatest in Africa. Studies have evaluated the role of variants in genes associated with HIV cell entry (such as the CCR5 A32 mutation). However, host genes are now known that mediate other HIV life cycle stages including viral integration, capsid formation and ihtracellular trafficking and budding. The impact of these these "HIV life cycle host genes" on HIV disease progression has not been well studied, particularly in African populations. We are in a unique position-to use specimens being collected in a clinical trial of HIV suppression in Africa to further study the role of host genetic factors in HIV disease progression in Africa. The Partners in Prevention Clinical Trial (Partners Study) is designed to assess the effect of genital herpes suppression with acyclovir in reducing HIV transmission. To accomplish this, 3000 HIV-discordant couples, in which the HIV- infected partner is co-infected with genital herpes (HSV-2) and CD4>250 cells/mm3, are being enrolled in diverse populations in Eastern and Southern Africa. Herpes suppression with daily acyclovir will be provided to the HIV-infected partner and both partners followed quarterly for 18-24 months. Whole blood specimens are being stored with informed consent for future host genetic studies on HIV disease. This large study presents a unique opportunity to evaluate genetic factors modifying HIV disease in Africans. Here we propose to use specimens from the Partners Study to evaluate host polymorphisms in genes that interact with HIV during life cycle stages including cell entry, nuclear targeting, capsid formation, cellular trafficking and budding. Our Specific Aims are: 1) Determine the frequency of specific genetic variants in the Partners study populations and in so doing, assess the capacity of the HapMap and other existing public SNP discovery databases to evaluate genetic variants across diverse African populations. 2) Apply multivariable linear regression and other statistical methods to the genetic data collected in Specific Aim 1 to evaluate the association of these genetic variants with disease progression as measured by viral load at enrollment, viral load change over follow-up and time to reach CD4<200 cells/mm3.