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

描述（由申请人提供）：在缺乏治疗的情况下，大多数感染HIV-1的人进展为艾滋病并最终死亡。然而，这种疾病进展的速度和特征有明显的差异，从几个月的快速进展到几年的无进展。越来越多的宿主遗传因子被发现可以改变HIV疾病的进展。但是这些遗传因素还没有在非洲人群中得到很好的研究，尽管非洲的艾滋病毒负担最大。研究已经评估了与HIV进入细胞相关的基因变异的作用（如CCR5 A32突变）。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“艾滋病毒生命周期宿主基因”对艾滋病毒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。我们处于一个独特的位置——利用在非洲HIV抑制临床试验中收集的标本，进一步研究宿主遗传因素在非洲HIV疾病进展中的作用。预防伙伴临床试验（伙伴研究）旨在评估用阿昔洛韦抑制生殖器疱疹在减少艾滋病毒传播方面的效果。为此，正在东部和南部非洲的不同人群中招募3000对不感染艾滋病毒的夫妇，其中感染艾滋病毒的伴侣同时感染生殖器疱疹（HSV-2）和CD4细胞/mm3 250个。将向感染艾滋病毒的伴侣每天提供阿昔洛韦抑制疱疹，双方每季度随访18-24个月。在知情同意的情况下，正在储存全血标本，供今后关于艾滋病毒疾病的宿主基因研究之用。这项大型研究提供了一个独特的机会来评估改变非洲人艾滋病毒疾病的遗传因素。在这里，我们建议使用伙伴研究的样本来评估宿主在生命周期阶段与HIV相互作用的基因多态性，包括细胞进入、核靶向、衣壳形成、细胞运输和出芽。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，并在此过程中评估HapMap和其他现有公共SNP发现数据库的能力，以评估不同非洲人群的遗传变异。2)对Specific Aim 1中收集的遗传数据应用多变量线性回归等统计方法，通过入组时的病毒载量、随访期间的病毒载量变化和达到CD4<200 cells/mm3的时间来评估这些遗传变异与疾病进展的关系。

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.