Host genetic determinants of HIV-AIDS susceptibility in a VA cohort

VA 队列中 HIV-AIDS 易感性的宿主遗传决定因素

基本信息

批准号：
8597354
负责人：
Sunil K Ahuja
金额：
--
依托单位：
SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-10-01 至 2014-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8597354
关键词：
17q12 AIDS/HIV problem Accounting Acquired Immunodeficiency Syndrome Address Adult Affect African American Age Aging Air Force Personnel Alcohol consumption Alcohols Alleles Anti-Retroviral Agents Antigen Receptors Antiviral Agents Ascaridil Award Behavior Binding Blood Platelets CCL3L1 gene CCR5 gene CD209 gene CD4 Positive T Lymphocytes Candidate Disease Gene Caring Cell Adhesion Molecules Cell Count Cells Cellular Immunity Cessation of life Chemokine (C-C Motif) Receptor 5 Chromosomes Clinical Code Cohort Studies Commit Comorbidity Complement Complex Consent Copy Number Polymorphism Cost Sharing DNA DNA Repository Data Data Analyses Defensins Dependence Dependency Dipeptidyl-Peptidase IV Discipline Disease Disease Progression Drug usage Enrollment Epidemic Epidemiologic Studies Epidemiologist Epidemiology Equilibrium Erythrocytes Evaluation Event Evolution Eye FCGR3B gene Failure Family Fc Receptor Funding Funding Agency GNB3 gene GTP-Binding Proteins Gap Junctions Generations Genes Genetic Genetic Determinism Genetic Epistasis Genetic Variation Genotype Goals Grant HIV HIV Infections HIV Seropositivity HIV-1 HLA-B Antigens HLA-C Antigens Hepatitis B Virus Hepatitis C virus Highly Active Antiretroviral Therapy Hispanic Americans Immune Immune response Immunologics Immunologist Immunology In Vitro Individual Infection Integration Host Factors Interferons Interleukin-12 Interleukin-2 Interleukin-7 Intrinsic factor Investigation Justice Knowledge Lead Learning Level of Evidence Life Life Cycle Stages Ligands Liver diseases Mannose Binding Lectin Mannose-Binding Lectins Manuscripts Mediating Medical center Messenger RNA Microbe Mutation N-terminal National Institute on Alcohol Abuse and Alcoholism Natural History Nature Observational Study Outcome Pathogenesis Pathway interactions Patients Perinatal Phenotype Play Population Predisposition Prevalence Process Production Public Health RNA Interference Recovery Relative (related person)Research Research Design Research Infrastructure Resources Risk Role Science Scientist Serine Protease Services Signal Transduction Site Source Specimen Surface System T-Lymphocyte TSG101 gene Testing Time Transcript Transducers Translating United States National Institutes of Health Universities Vaccines Validation Variant Veterans Vial device Viral Viral Load result Work antiretroviral therapy apolipoprotein E-4 base bench to bedside biobank chemokine chemokine receptor clinical care clinically relevant cohort cytokine experience gene interaction genetic variant genome wide association study genome-wide human disease improved in vivo indexing innovation insight interest medical schools member multidisciplinary novel promoter protective effect public health relevance racial and ethnic receptor response risk variant skills success therapy development tool transcription factor translational study transmission process vaccine efficacy

项目摘要

DESCRIPTION (provided by applicant): There is growing evidence that the host genetic make-up of an individual is a strong determinant of HIV/AIDS susceptibility during untreated HIV infection and immune recovery during highly active antiretroviral therapy (HAART). We will use state-of-the-art powerful genetic and statistical tools and targeted candidate gene approaches to identify genetic factors that influence HIV-AIDS susceptibility as well as immune recovery during highly active antiretroviral therapy (HAART) in a large cohort of adults from the VA, namely VA Aging Cohort Study (VACS). These studies will thus (a) uncover complex host gene-gene interactions that influence HIV-1 pathogenesis and immune recovery during HAART in vivo; (b) determine the relative contribution to these determinants to the HIV-1 epidemic at the population level; (c) translate these findings to real life practical issues such as improved clinical care of patients via genetic-based prognostication of AIDS as well as immune recovery during HAART; and (d) the influence of alcohol and age in immune depletion/recovery. In the current application we will test the overall hypothesis that (I) expression of members of the CD4 - CD4 ligand - CCR5 - CCR5 ligand nexus, including relevant transducers of coreceptor signals, will alter HIV/AIDS susceptibility and immune recovery during HAART (aim #1); (II) expression of and interaction between selected candidate genes that influence innate and adaptive immune responses will alter HIV-AIDS susceptibility and immune recovery during HAART (aim #2). These include genes (i) at the MHC and KIR locus; (ii) encoding cellular intrinsic factors (TRIM5 and Apobec3 family); (iii) involved in the HIV life cycle such as PPIA and TSG101; (iv) identified as HIV dependency factors (HDF), and (iv) Copy Number Variation (CNV) at the chemokine gene-rich locus on chromosome 17q12, complement components (C4A and C4B), Fc receptors (FCGR3), and defensins. Thus, this proposal seeks approval for the use of specimens at VA Central biorepository to support a collaborative study to explore the genetic mechanisms underlying HIV/AIDS susceptibility and immune recovery during HAART by amalgamating the unique skills and resources of the research teams at the VA Center for AIDS and HIV Infection at San Antonio, TX (PI: Dr Ahuja) and Yale University School of Medicine, New Haven, CT (PI: Dr Justice). PUBLIC HEALTH RELEVANCE: The studies proposed will provide new insights into the host factors that influence susceptibility to HIV and AIDS, and these findings could provide new ways to develop therapies and vaccines.

描述（由申请人提供）：越来越多的证据表明，个体的宿主基因组成是在未经治疗的艾滋病毒感染过程中艾滋病毒/艾滋病敏感性的强大决定因素，在高度活跃的抗逆转录病毒疗法（HAART）期间的免疫恢复。我们将使用最先进的强大遗传和统计工具以及有针对性的候选基因方法来鉴定在高度活跃的抗逆转录病毒疗法（HAART）中影响HIV-AID易感性以及免疫恢复的遗传因素，这是VA的大量成年人，即VA的大量成年人，即VA衰减研究（VACS）。因此，这些研究将（a）发现影响HIV-1发病机理和体内HAART的免疫恢复的复杂宿主基因相互作用；（b）确定对这些决定因素在人群水平上对HIV-1流行的相对贡献；（c）将这些发现转化为现实生活中的实际问题，例如通过基于遗传的艾滋病预后以及HAART期间的免疫恢复来改善患者的临床护理；（d）酒精和年龄在免疫消耗/恢复中的影响。在当前的应用中，我们将测试总体假设，即（i）CD4 -CD4配体-CCR5 -CCR5 -CCR5配体连接的表达，包括共受体信号的相关换能器，将改变HIV/AIDS在HAART期间的HIV/AIDS敏感性和免疫恢复（AIM＃1）；（ii）影响先天和适应性免疫反应的选定候选基因之间的表达和相互作用将改变HAART期间HIV-AID的敏感性和免疫恢复（AIM＃2）。这些包括MHC和KIR基因座的基因（i）；（ii）编码细胞内在因子（TRIM5和APOBEC3家族）；（iii）参与HIV生命周期，例如PPIA和TSG101；（iv）在趋化因子基因17q12染色体，补体成分（C4A和C4B），FC受体（FCGR3）和Defensins上的趋化因子基因富基因基因座的艾滋病毒依赖性因子（HDF）和（iv）拷贝数变化（CNV）。因此，该提案寻求批准在VA中央生物座位上使用标本，以支持一项协作研究，以探索HAART期间HAART的HIV/AIDS敏感性和免疫恢复的遗传机制，通过将VA AIDS和HIV Invection for VA Invection in San Antonio and Have and Haart的独特技能和资源合并到San Antonio and san Antx（phan Antx（p））， CT（PI：Justice博士）。公共卫生相关性：提出的研究将提供有关影响艾滋病毒和艾滋病易感性的宿主因素的新见解，这些发现可以提供开发疗法和疫苗的新方法。