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

具有极端 HIV-1 传播表型的非洲人的完整基因组变异

基本信息

批准号：
8137513
负责人：
Jairam Rao Lingappa
金额：
$ 98.88万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8137513
关键词：
Address Adjuvant Affect Africa South of the Sahara African Age Aliquot Behavioral Biological Factors Blood CCR5 gene Candidate Disease Gene Cells Chemokine (C-C Motif) Receptor 5 Clinical Complex Couples DNA Sequence Data Databases Development Economic Burden Environmental Risk Factor Epidemiologic Factors Epidemiology European Evaluation Event Exposure to Frequencies Gender Gene Expression Gene Frequency Genes Genetic Genetic Variation Genome Genomics Genotype HIV HIV-1 Heritability Heterosexuals Host resistance Immune response Incidence Individual Infection Infection Control Male Circumcision Mediating Minor Mutation Natural Resistance Observational Study Participant Pathway interactions Phenotype Plasma Population Predisposition Prevention Preventive Intervention Public Health Recruitment Activity Regulator Genes Research Design Resistance Risk Sampling Sexual Partners Sexual Transmission Specimen Staging Technology Testing Universities Unsafe Sex Vaccine Adjuvant Variant Virus Washington Whole Blood cohort design follow-up genetic risk factor genetic variant genital secretion genome sequencing genome wide association study genome-wide high risk insight next generation novel pandemic disease pathogen prevention clinical trial repository resistance factors social success trait transmission process

项目摘要

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. PUBLIC HEALTH RELEVANCE: We seek to better understand host genetic factors that mediate natural host resistance to HIV-1 infection. To do this, we propose to sequence the complete genomes of 50 individuals with very high exposure to HIV-1 who did not become infected, and 50 individuals with low HIV-1 exposure who did become HIV-1 infected. High priority genetic changes in this sequence data that appear to be related to host susceptibility or resistance to HIV-1 infection will be further studied to confirm their effect on HIV-1 transmission risk.

描述（由申请人提供）：解释宿主对 HIV-1 感染的自然抵抗力（尽管广泛性接触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 感染自然抵抗力的宿主基因变异，但很少在非洲人群体（受这一流行病影响最严重）中进行此类研究，也没有全面的全基因组评估来捕获常见和低水平的人群。宿主遗传变异影响 HIV-1 感染的频率已在任何人群中进行过。原因之一是此类研究必须控制改变 HIV-1 暴露风险的流行病学因素（例如，感染者的血浆 HIV-1 水平，以及未感染者的男性包皮环切状况）。这些暴露数据必须从 HIV-1 感染者和 HIV-1 未感染者的性伴侣处收集，因此需要招募 HIV-1 血清不一致的夫妇（一方感染 HIV-1，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 年里，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 个大型非洲 HIV-1 血清不一致异性夫妇队列，其中包括近 8,600 对夫妇（17,200 人），每组有 12 至 36 名艾滋病毒感染者。每月或每季度进行数月的随访，以评估最初未感染 HIV-1 的伴侣的 HIV-1 血清转化情况。这些群体的中央样本库位于华盛顿大学，目前保存着超过一百万等分的各种临床样本类型，包括用于基因组研究的全血。还从所有参与者收集了流行病学、临床和行为数据，以便详细评估影响 HIV-1 传播风险的 HIV-1 暴露因素。在这里，我们建议利用这一独特的现有样本和数据存储库以及“下一代”DNA测序技术对影响HIV-1传播的宿主基因组因素进行全面分析。为了广泛捕获宿主遗传风险因素，我们建议对 50 名在低水平 HIV-1 暴露下感染 HIV-1 的个体和 50 名尽管异性接触水平高但对 HIV-1 感染具有抵抗力的个体进行基因组测序。病毒。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。然后，将从这些序列数据中鉴定出的一组高优先级变异在剩余队列中进行基因分型，以鉴定非洲人中与自然宿主易感性和对 HIV-1 传播的抵抗力相关的宿主遗传变异。这些数据可以提供重要的见解，特别是对于制定 HIV-1 预防干预措施（例如疫苗佐剂或基因表达调节剂）以广泛引发宿主对 HIV-1 感染的抵抗力。公共卫生相关性：我们寻求更好地了解介导宿主对 HIV-1 感染自然抵抗力的宿主遗传因素。为此，我们建议对 50 名 HIV-1 暴露率极高但未感染的个体和 50 名 HIV-1 暴露率低但确实感染 HIV-1 的个体的完整基因组进行测序。该序列数据中似乎与宿主对 HIV-1 感染的易感性或抵抗力相关的高度优先的遗传变化将被进一步研究，以确认其对 HIV-1 传播风险的影响。