Host Genetics of HIV-1 Subtype C Infection, Progression, and Treatment in Africa

描述（由申请人提供）：先前关于HIV/AIDS宿主易感基因的研究主要集中在感染HIV-1B的高加索男性。这表明与风险最大的人口，即南部非洲感染艾滋病毒-1C的妇女，存在重大脱节。关于宿主遗传因素在非洲人群中非B HIV-1感染和进展或HAART反应中的作用知之甚少。博茨瓦纳在使用高效抗逆转录病毒疗法方面处于该区域的领先地位。我们假设，影响HIV-1疾病风险的遗传因素可能与感染HIV-1 C亚型的南部非洲异性恋者不同，并可能部分解释较高的患病率，疾病模式的差异以及与HAART相关的不良事件谱。我们建议评估宿主遗传变异在已知艾滋病限制性基因（ARG）、先天免疫因子（Cul 5、KIR、APOBEC 3G、APOBEC 3F和TRIMS及相关基因家族成员）、补体因子、线粒体中的作用！基因、选定的免疫反应调节剂和HIV-1共受体（细胞因子和细胞因子受体、趋化因子和趋化因子受体）、HLA 1类基因和HIV-1生命周期所需的宿主因子对以下方面的影响：1）对HIV-1C感染的易感性; 2）HIV感染者中CD 4 T细胞和HIV-1C RNA水平的轨迹; 3）HAART在AIDS患者中的疗效;和4）在HAART治疗和未治疗的人中发展特定的艾滋病定义条件。具体目标：1。目的研究HIV-1C易感性基因中功能性基因型变异的影响. 2.研究在开始抗逆转录病毒治疗前，选定基因的功能基因型变异对HIV-1感染成人的CD 4 + T细胞和HIV RNA水平的影响。3.研究选定基因的功能基因型变异对HAART疗效和不良事件的作用。4.研究功能性基因型变异在特定艾滋病定义条件下的作用。在非洲群体中发现和表征艾滋病抗性基因至少从四个方面来看是至关重要的：i）涉及将改变感染风险和影响发病机制的宿主因素; //）鉴定适合于疗法开发的新宿主途径; i）定义ART功效和不良事件的混杂因素;和iv）为非洲ART患者的临床管理提供协变量。

DESCRIPTION (provided by applicant): Previous studies on host susceptibility genes for HIV/AIDS have focused on Caucasian men infected with HIV-1B. This represents a major disconnect with populations at greatest risk, which are women infected with HIV-1C in southern Africa. Little is known about the role of host genetic factors on non-B HIV-1 infection and progression or on HAART response in African populations. Botswana has led the region in the use of HAART. We hypothesize that genetic factors affecting risk of HIV-1 disease may be different i n southern African heterosexuals infected with HIV-1 subtype C and may explain in part the higher prevalence, differences in disease patterns, and the spectrum of adverse events related to HAART. We propose to evaluate the role of host genetic variation in known AIDS restriction genes (ARGs), innate immunity factors (Cul5, KIR, APOBEC3G, APOBEC3F, and TRIMS and related gene family members), complement factors, mitochondria! genes, selected immune response modifiers and HIV-1 co-receptors (cytokines and cytokine receptors, chemokines and chemokine receptors), HLA class 1 genes and host factors required for HIV-1 life cycle on: 1) susceptibility to HIV-1 C infection; 2) trajectories of CD4 T cell and HIV-1 C RNA levels in HIV-infected persons; 3) efficacy of HAART in persons with AIDS; and 4) development of specific AIDS-defining conditions in HAART-treated and untreated persons. Specific Aims: 1. To investigate the influence of functional genotypic variants in selected genes on susceptibility to HIV-1 C. 2. To investigate the influence of functional genotypic variants in selected genes on the trajectory of CD4+ T cell and HIV RNA levels in HIV-1 infected adults before initiating ARV treatment. 3. To investigate the role of functional genotypic variants in selected genes on HAART efficacy and adverse events. 4. To investigate the role of functional genotypic variants on specific AIDS-defining conditions. AIDS resistance gene discovery and characterization in African cohorts is critical from at least four perspectives: /') to implicate host factors that would alter risk for infection and influence pathogenesis; //) to identify new host avenues suitable for therapy development, /'/'/) to define confounders of ART efficacy and adverse events; and iv) to provide co-variates for clinical management of ART patients in Africa.