Complete Genome Variation in Africans with Extreme HIV-1 Transmission Phenotypes

描述（由申请人提供）：解释宿主对HIV-1感染的天然抗性（尽管广泛性暴露于病毒，但仍未感染的个体）的挑战仍未完全解决。虽然已经确定了一些影响对HIV-1感染的天然抵抗力的宿主遗传变异，但在非洲人（受这一流行病影响最大）的队列中进行的此类研究很少，并且没有在任何人群中进行全面的全基因组评价，以捕获影响HIV-1感染的常见和低频宿主遗传变异。其中一个原因是这些研究必须控制流行病学因素（例如，受感染伴侣的血浆HIV-1水平和未受感染伴侣的男性包皮环切术状况），这些因素改变了HIV-1暴露风险。这些暴露数据必须从HIV-1感染者和HIV-1未感染者的性伴侣中收集，这需要招募HIV-1血清不一致的夫妇（一方伴侣HIV-1感染，另一方未感染）-这是一项昂贵且复杂的研究设计。在过去的6年中，在进行2项HIV-1预防临床试验和一项观察性研究的过程中，我们招募了3大组非洲HIV-1血清不一致的异性恋夫妇，包括近8，600对夫妇（17，200人），每个人每月或每季度随访12至36个月，以评估最初未感染HIV-1的伴侣的HIV-1血清转换。这些队列的中央标本库位于华盛顿大学，目前保存了超过100万份各种临床样本类型的等分试样，包括用于基因组研究的全血。还从所有参与者中收集了流行病学、临床和行为数据，以便对影响HIV-1传播风险的HIV- 1暴露因素进行详细评估。在这里，我们建议使用这一独特的现有标本和数据库和“下一代”DNA测序技术进行全面的分析宿主基因组因素影响HIV-1的传播。为了广泛地捕获宿主遗传风险因素，我们建议对50名HIV-1感染者的基因组进行完全测序，这些人感染HIV-1的暴露水平较低，50名对HIV-1感染具有抵抗力的人，尽管异性接触病毒的水平较高。这种极端表型方法将最大限度地提高我们捕获与HIV-1传播相关的宿主遗传因素的能力。从这些序列数据中识别出的一组高优先级变异将在剩余的队列中进行基因分型，以识别非洲人中与自然宿主易感性和对HIV-1传播的抗性相关的宿主遗传变异。这些数据可以提供关键的见解，特别是对开发HIV-1预防干预措施（如疫苗佐剂或基因表达调节剂），以广泛地引发宿主对HIV-1感染的抵抗力。

DESCRIPTION (provided by applicant): The challenge of explaining natural host resistance to HIV-1 infection (individuals who remain uninfected despite extensive sexual exposure to the virus) remains incompletely addressed. While some host genetic variants that influence natural resistance to HIV-1 infection have been identified few such studies have been conducted in cohorts of Africans (who are most impacted by this pandemic), and no comprehensive genome-wide evaluation that captures common and low-frequency host genetic variation influencing HIV-1 infection has been done in any population. One reason for this is that such studies must control for epidemiologic factors (e.g., level of plasma HIV-1 in the infected parter, and male circumcision status in the uninfected partner) that modify HIV-1 exposure risk. These exposure data must be collected from both the HIV-1 infected and HIV-1 uninfected sexual partner necessitating recruitment of HIV-1 serodiscordant couples (one partner HIV-1 infected and the other uninfected) - a costly and complex study design. Over the past 6 years, in the course of conducting 2 HIV-1 prevention clinical trials and an observational study, we have recruited 3 large cohorts of African HIV-1 serodiscordant heterosexual couples encompassing nearly 8,600 couples (17,200 individuals) each with 12 to 36 months of monthly or quarterly follow-up to evaluate for HIV-1 seroconversion in the initially HIV-1 uninfected partner. The central specimen repository for these cohorts is located at the University of Washington and currently holds over a million aliquots of a wide range of clinical sample types including whole blood for genomic studies. Epidemiologic, clinical and behavioral data have also been collected from all participants permitting detailed evaluation of HIV- 1 exposure factors affecting risk of HIV-1 transmission. Here we propose to use this unique existing specimen and data repository and "next generation" DNA sequencing technology to perform a comprehensive analysis for host genomic factors affecting HIV-1 transmission. In order to broadly capture host genetic risk factors, we propose to completely sequence the genomes of 50 individuals who became HIV-1 infected with low levels of HIV-1 exposure and 50 individuals resistant to HIV-1 infection despite high levels of heterosexual exposure to the virus. This extreme phenotype approach will maximize our power to capture host genetic factors associated with HIV-1 transmission. A set of high priority variants identified from these sequence data will then be genotyped in the remaining cohort to identify host genetic variants in Africans associated with natural host susceptibility and resistance to HIV-1 transmission. These data could provide critical insights particularly toward developing HIV-1 prevention interventions (e.g. vaccine adjuvants or gene expression modulators) to broadly elicit host resistance to HIV-1 infection.