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

• 批准号: 8486385
• 负责人: Jairam Rao Lingappa
• 金额: $ 58.25万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 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/8486385
• 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

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.

描述（由申请人提供）：解释自然宿主对HIV-1感染的抗药性（尽管对病毒的性暴露广泛，但仍未感染的人仍未感染）。尽管已经确定了某些影响对HIV-1感染的自然抗性的宿主遗传变异，但在非洲人的同龄人中很少进行此类研究（他们受到这一大流行的影响最大），并且没有捕获任何人群对HIV-1进行影响HIV-1的常见和低频宿主遗传感染的全面评估。这样做的一个原因是，这种研究必须控制流行病学因素（例如，感染parter中的血浆HIV-1水平，未感染的伴侣中的男性割礼状态），以改变HIV-1暴露风险。这些暴露数据必须从HIV-1感染和HIV-1未感染的性伴侣中收集，这些伴侣需要招募HIV-1 SerioDiscordant夫妇（一种感染了HIV-1的伴侣HIV-1，另一个未感染的伴侣）是一项昂贵且复杂的研究设计。在过去的六年中，在进行2次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 eriodiscordant异性夫妇，包括近8,600对夫妇（17,200个人（17,200个人），每个人每月一次或每季度的季度随访，以评估HIV-1的每季度或每季度，以评估seroconsiv-1的启动HIV-1，该合作伙伴在1个启动HIV-1中均在1个启动HIV-1中启动HINF。这些队列的中央标本存储库位于华盛顿大学，目前拥有超过一百万个等分试样的各种临床样本类型，包括全基因组研究。还从所有参与者那里收集了流行病学，临床和行为数据，允许对影响HIV-1传播风险的HIV-1暴露因素进行详细评估。在这里，我们建议使用这种独特的现有标本和数据存储库以及“下一代” DNA测序技术来对影响HIV-1传播的宿主基因组因素进行全面分析。为了广泛捕获宿主的遗传危险因素，我们建议完全对50个人的基因组序列，这些个体被感染了低水平的HIV-1暴露于HIV-1和50个对HIV-1感染具有抗性HIV-1的个体，尽管对病毒的异性含量很高。这种极端的表型方法将最大程度地利用我们捕获与HIV-1传播相关的宿主遗传因素的能力。从这些序列数据中鉴定出的一组高优先级变体将在其余人群中进行基因分型，以鉴定与自然宿主易感性和对HIV-1传播的抗性相关的非洲人中的宿主遗传变异。这些数据可以提供关键的见解，特别是针对开发HIV-1预防干预措施（例如疫苗辅助或基因表达调节剂），以广泛引起宿主对HIV-1感染的抗性。