Host Genetic Epidemiology in HIV-1-Discordant African Couples and Other Cohorts

HIV-1 不一致的非洲夫妇和其他群体的宿主遗传流行病学

基本信息

批准号：
8070218
负责人：
Jianming Tang
金额：
$ 50.09万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-07 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8070218
关键词：
17q11 19q13.4 3p21 AIDS/HIV problem Accounting Acquired Immunodeficiency Syndrome Address African African American Alleles Ancillary Study Antigen Presentation Antigens Arts Bioinformatics CCL3 gene CCL3L1 gene CCL4 gene CCR CCR5 gene Candidate Disease Gene Caucasians Caucasoid Race Cells Cellular Immunity Chromosomes, Human, Pair 3 Clinical Collaborations Complex Copy Number Polymorphism Couples Critical Pathways Cytotoxic T-Lymphocytes DNA Sequence Data Development Disease Epidemiologic Studies Epidemiology Ethnic Origin European Evolution Family Frequencies Gene Family Genes Genetic Genetic Determinism Genetic Polymorphism Genetic Variation Genetic screening method Genomics Goals HIV HIV vaccine HIV-1 HLA Class I Genes HLA G antigen HLA-A gene HLA-B Antigens HLA-C Antigens Haplotypes Health Heterosexuals Histocompatibility Antigens Class I Human Human Genetics Immune Immune Response Genes Immunogenetics Immunologics Individual Infection Infection Control Interruption Intervention Trial Investigation Joints Knowledge Laboratories Leukocytes Ligands Link MHC Class I Genes Mediating Modeling Monitor Natural Killer Cells Natural experiment Nature Outcome Outcome Measure Pathway interactions Phenotype Plasma Population Portraits RANTES Reporting Research Research Infrastructure Research Project Grants Resources Risk Role Rwanda Sample Size Scientist Services Shapes Single Nucleotide Polymorphism Solid Specimen Staging Statistical Methods System Techniques Testing Time Translating Uganda Vaccine Design Vaccines Variant Viral Viral Load result Virus Work Zambia base beta-Chemokines biomedical scientist chemokine chemokine receptor cohort cytotoxicity design gene environment interaction genetic epidemiology genetic variant genome database immunoregulation indexing innovation insight men who have sex with men microbicide non-genetic novel receptor repository response tool transmission process viral RNA

项目摘要

DESCRIPTION (provided by applicant): Human genetic polymorphisms influence the occurrence and evolution of HIV-1 infection. The goals of the Office of AIDS Research FY 2008 Plan for HIV-Related Research include the identification of host genetic factors that explain highly variable responses to the infection and its sequelae. This proposed initiative will provide new insight into key genetic determinants of these responses. This new knowledge will translate into guidance for vaccinologists grappling with the development of HIV vaccines and potential population differences in response to them, for biotechnologists pursuing strategies for immunomodulation of co-receptor and ligand molecules, and for clinicians designing and analyzing intervention trials. Genetic determinants will be studied primarily in infected and susceptible populations in Zambia, Uganda, and Rwanda and secondarily in European and African-American HIV/AIDS cohorts. Primary work will concentrate on a unique assembly of 1400 heterosexually active African couples who are discordant for HIV-1 infection (i.e., one partner HIV-1- positive and one negative). Through investigation of couples, responses of two hosts successively infected with related virus can be observed on a previously unequaled scale. This natural experiment permits powerful hypothesis testing for genetic effects on transmission and viral evolution in initially untreated individuals. Specific aims address genes in two pathways critical for the response to the virus. The first aim covers genes in the HLA class I antigen-presenting pathway (HLA-A, HLA-B and HLA-C) along with those in the leukocyte receptor complex (LRC) gene family including KIR genes and LILRB1 in the natural killer cell pathway. The second aim covers genes in the pathway for expression of the HIV-1 chemokine co-receptor and its ligands (CCR2, CCR5, CCL3, CCL3L1, CCL4, CCL4L1, and CCL5). Related new candidate genes will be considered. Public bioinformatics databases, genome-level sequencing services, and state-of-the-art laboratory techniques will be used to detect polymorphisms within the selected loci. Principal outcome measures include time to seroconversion in exposed HIV-1-negative partners and level of plasma viral RNA early in infection. Individual African cohorts will support independent hypothesis-testing, and powerful inferences may be drawn from data on judiciously aggregated cohorts. Analyses will emphasize predicted interactions between products of receptor and ligand genes. Simultaneous effects of multiple markers on outcomes will be examined. Comparisons effects across HIV-1 subtypes within Africans and across ethnic boundaries will be made. Through the application's innovative statistical approaches that take advantage of haplotype recognition, complex interactions and potential false discovery, a more comprehensive portrait of genetic determinants in HIV/AIDS will emerge. The carefully assembled phenotype data and specimen repository will also provide a solid infrastructure for further genetic/genomic research at the epidemiologic level and for collaborations with basic scientists aimed at probing the functional correlations of well-documented immunogenetic relationships. PROJECT NARRATIVE This genetic epidemiologic research on variants in key human immune response genes will help explain why individuals differ so widely in the ease with which they become infected with HIV and the rate at which they progress to disease. The knowledge is most directly relevant to the health of African populations. It will also translate into guidance for biomedical scientists who are grappling with the development of HIV vaccines and potential population differences in response to them, pursuing strategies for modulation molecules involved in viral entry into cells, and designing and analyzing intervention trials.

描述（申请人提供）：人类遗传多态性影响HIV-1感染的发生和演变。艾滋病研究办公室2008财年艾滋病毒相关研究计划的目标包括确定宿主遗传因素，以解释对感染及其后遗症的高度可变的反应。这项拟议的举措将为这些反应的关键遗传决定因素提供新的见解。这些新知识将转化为疫苗学家的指导，帮助他们解决艾滋病毒疫苗的开发和应对疫苗的潜在人群差异，为生物技术学家寻求共同受体和配体分子的免疫调节策略，以及为临床医生设计和分析干预试验提供指导。遗传决定因素将主要在赞比亚、乌干达和卢旺达的感染者和易感人群中进行研究，其次在欧洲和非裔美国人的艾滋病毒/艾滋病队列中进行研究。主要工作将集中于 1400 对异性恋活跃的非洲夫妇的独特集合，这些夫妇的 HIV-1 感染情况不一致（即，一对伴侣 HIV-1 呈阳性，一对阴性）。通过对夫妇的调查，可以观察到连续感染相关病毒的两个宿主的反应，其规模是前所未有的。这项自然实验可以对最初未经治疗的个体的传播和病毒进化的遗传影响进行强有力的假设检验。具体目标是针对对病毒反应至关重要的两条途径中的基因。第一个目标涵盖 HLA I 类抗原呈递途径（HLA-A、HLA-B 和 HLA-C）中的基因以及白细胞受体复合物 (LRC) 基因家族中的基因，包括自然杀伤细胞中的 KIR 基因和 LILRB1途径。第二个目标涵盖 HIV-1 趋化因子辅助受体及其配体（CCR2、CCR5、CCL3、CCL3L1、CCL4、CCL4L1 和 CCL5）表达途径中的基因。将考虑相关的新候选基因。公共生物信息学数据库、基因组测序服务和最先进的实验室技术将用于检测选定基因座内的多态性。主要结果指标包括暴露的 HIV-1 阴性伴侣的血清转化时间和感染早期血浆病毒 RNA 水平。个别非洲群体将支持独立的假设检验，并且可以从明智汇总的群体数据中得出强有力的推论。分析将强调受体和配体基因产物之间的预测相互作用。将检查多个标记物对结果的同时影响。将比较非洲人体内和不同种族之间 HIV-1 亚型的影响。通过该应用程序的创新统计方法，利用单倍型识别、复杂的相互作用和潜在的错误发现，将出现艾滋病毒/艾滋病遗传决定因素的更全面的描述。精心组装的表型数据和标本存储库还将为流行病学层面的进一步遗传/基因组研究以及与基础科学家的合作提供坚实的基础设施，旨在探索有据可查的免疫遗传学关系的功能相关性。项目叙述这项针对人类关键免疫反应基因变异的遗传流行病学研究将有助于解释为什么个体在感染艾滋病毒的难易程度和疾病进展的速度方面存在如此巨大的差异。这些知识与非洲人口的健康最直接相关。它还将为生物医学科学家提供指导，帮助他们解决艾滋病毒疫苗的开发和应对疫苗的潜在人群差异，寻求参与病毒进入细胞的调节分子的策略，以及设计和分析干预试验。