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Host Genetic Determinants of HIV Pathogenesis

Host Genetic Determinants of HIV Pathogenesis
HIV发病机制的宿主遗传决定因素
批准号:
8119291
负责人:
Sunil K Ahuja
金额:
$70.56万
依托单位国家:
美国
项目类别:
财政年份:
2010
资助国家:
美国
项目状态:
已结题
起止时间:
2010-09-07 至 2012-08-31
关键词:
AIDS/HIV problemAccountingAcquired Immunodeficiency SyndromeAddressAntibodiesAttentionBehaviorBiologyCCL3L1 geneCCL4 geneCCR5 geneCD8B1 geneCandidate Disease GeneCaringCellsChromosomes, Human, Pair 12ClinicClinicalCommunitiesComplementComplementary DNAComplexCoupledCytotoxic T-LymphocytesDefensinsDevelopmentDiseaseDoseEpidemicEpidemiologyEvaluationEventEvolutionFigs - dietaryFundingGTP-Binding ProteinsGap JunctionsGene AmplificationGene DosageGenesGeneticGenetic DeterminismGenetic VariationGenomeGenotypeGoalsHIVHIV Envelope Protein gp120HIV-1HaplotypesHighly Active Antiretroviral TherapyHomeostasisHumanImmuneImmune responseImmunityImmunogeneticsImmunologyIndividualInfectionInfluentialsIntegration Host FactorsInterferonsInterleukin-15Interleukin-2Interleukin-7InvestigationKnowledgeLifeLigandsLightLinkMaintenanceMediatingModelingMolecular BiologyMolecular GeneticsMourningNatureParentsPathogenesisPatientsPhilosophyPlayPopulationPopulation GeneticsPredispositionProcessProtein IsoformsPublic HealthRegulationRegulatory T-LymphocyteRelative (related person)ResearchResearch Ethics CommitteesResourcesRiskRoleRunningSignal TransductionSpecimenStudy SectionSystemT-LymphocyteTestingTimeTransducersTranslatingTranslationsUtahVaccine DesignVaccinesVariantViralViral Load resultViral PhysiologyVirusWorkWritingalpha-Defensinsarmbasebiological systemschemokineclinical carecohortcytokinedesignessaysexpedited reviewforgingforkhead proteingazegene interactiongenetic epidemiologyimprovedin vivoinsightmemberresponseskillsstatisticstooltranscription factorvaccine developmentvaccine evaluationvirology

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中文摘要
翻译
越来越多的证据表明,个体的宿主遗传构成是一个强有力的决定因素, 艾滋病毒/艾滋病易感性。我们整合了遗传学、免疫学和进化论, (a)揭示影响体内HIV-1发病机制的复杂宿主基因-基因相互作用; (b)确定这些决定因素在人口一级对艾滋病毒-1流行病的相对贡献;(c) 将这些发现转化为真实的生活中的实际问题,例如通过基于遗传学的方法改善患者的临床护理, 艾滋病的统计以及疫苗试验的设计和评价;以及(d)阐明 免疫相关的体内保护性抗HIV反应,可以为合理的疫苗设计建模。 在本申请中,我们将测试以下总体假设:(I)CD 4-CD 4-T细胞的成员的表达, 配体-CCR 5-CCR 5配体关系,包括辅助受体信号的相关转导物,将改变 艾滋病毒/艾滋病易感性(目标1);(二)影响T细胞动力学的候选基因的表达, 调控将改变艾滋病毒/艾滋病易感性(目标#2);(III)艾滋病毒/艾滋病易感性与基因有关 剂量的α-防御素(目标#3)。在目标4中,我们将探索将宿主遗传学置于更广泛的环境中的方法。 框架,并将确定其对艾滋病预后、T细胞动力学和其他公众的影响 流行病的健康方面。因此,本提案寻求资金,以支持一项合作研究, 通过融合独特的技能和资源, 两个不同的研究小组,即遗传学(UTHSCSA),流行病学/病毒学/统计学(WHMC), 群体遗传学(犹他州)和免疫学/病毒学(范德比尔特)。这项研究将利用现有的, 匿名无关联的人类标本IRB已批准对这些标本进行遗传学研究, 先前根据45 CFR 46.110授权的快速审查获得,并且是 已批准的IRB提案。
英文摘要
There is growing evidence that the host genetic make-up of an individual is a strong determinant of HIV/AIDS susceptibility. We have integrated genetics, immunology, and evolution, and used them as powerful tools to (a) uncover complex host gene-gene interactions that influence HIV-1 pathogenesis 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 geneticbased prognostication of AIDS as well as design and evaluation of vaccine trials; and (d) shed light on the immune correlates of a protective anti-HIV response in vivo that can be modeled for rational vaccine design. 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 (aim #1); (II) expression of candidate genes that influence T cell dynamics and regulation will alter HIV/AIDS susceptibility (aim #2); and (III) HIV/AIDS susceptibility is linked to the gene dose of alpha-defensins (aim #3). In aim #4, we will explore means to place host genetics in a broader framework, and will determine their influence on AIDS prognostication, T cell dynamics and other public health aspects of the epidemic. Thus, this proposal seeks funds to support a collaborative study to explore the genetic mechanisms underlying HIV/AIDS susceptibility by amalgamating the unique skills and resources of two different research teams, namely genetics (UTHSCSA), epidemiology/virology/statistics (WHMC), population genetics (Utah) and immunolog/virology (Vanderbilt). This study will utilize pre-existing, anonymous, unlinked human specimens. IRB approval for genetic study of these specimens has been previously obtained under expedited review authorized by 45 CFR 46.110, and is a continuation of an existing approved IRB proposal.
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Host genetic determinants of HIV-AIDS susceptibility in a VA cohort
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