High Specificity HIV-1 Markers Predictive of Neuro-AIDS
预测神经艾滋病的高特异性 HIV-1 标记物
基本信息
- 批准号:8145279
- 负责人:
- 金额:$ 67.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-09-30 至 2015-06-30
- 项目状态:已结题
- 来源:
- 关键词:AIDS Dementia ComplexAcquired Immunodeficiency SyndromeAffectAreaBindingBinding SitesBioinformaticsBrainCannabinoidsCell ProliferationCellsCentral Nervous System DiseasesCessation of lifeClinicalCocaineCognitiveComorbidityDNA-Directed DNA PolymeraseDatabasesDevelopmentDiseaseDisease ProgressionEvolutionFunctional disorderGene ExpressionGene MutationGenetic TranscriptionGenomeGenomicsHIVHIV Envelope Protein gp120HIV-1Highly Active Antiretroviral TherapyImmune systemIndividualInfectionLong Terminal RepeatsLongitudinal StudiesMinorModelingMolecular CloningMutationNeurocognitiveNeurological statusNucleotidesOrganPathogenesisPatientsPeripheral Blood Mononuclear CellPhenotypePlasmaPolymerase Chain ReactionPopulationPopulation StudyProcessPropertyProteinsProvirusesRecording of previous eventsResponse LatenciesSamplingSerumSignal PathwaySingle Nucleotide PolymorphismSingle Nucleotide Polymorphism in Coding SequenceSpecificityStagingStructureSubstance abuse problemSubstance of AbuseTechnologyTherapeuticTissuesTrans-ActivatorsTranscriptional RegulationTransfectionTranslational ResearchVariantViralViral GenesViral PathogenesisVirusVisitWorkantiretroviral therapybrain tissuecell typecohortdemographicsdrug of abusegenetic elementinnovationmolecular markermotor disordernervous system disorderperipheral bloodpromoterpublic health relevanceresearch studyresidenceresponsesocialtoolvirus host interaction
项目摘要
DESCRIPTION (provided by applicant): Pathogenesis and disease progression subsequent to human immunodeficiency virus type 1 (HIV-1) infection of the immune system, brain, and other end organs is dependent on viral entry and replication in specific cell populations within these compartments that cause celular dysfunction or death by a variety of direct and/or indirect mechanisms. These virus-host interactions can be regulated by numerous factors, including viral binding and entry, host cell proliferation and activation, cellular differentiation, antiretroviral therapy status, substances of abuse, and the action of viral and cellular proteins that interface with the long terminal repeat (LTR) and to each other to regulate viral expression. The capacity of HIV-1 to replicate is further affected by the evolution of viral quasispecies. Studies have indicated that naturally-occurring sequence variation within the LTR influences the ability of the viral promoter to drive viral expression by altering functional interactions with cellular and viral trans-activators. Recent studies have suggested the possibility that genetic alterations within the HIV-1 genome may correlate with either the stage of HIV-1 disease, neurologic status, and/or organ compartmentalization. However, many of these studies involved cross population analyses of clinical samples from a small number of patients in the pre-HAART era, rather than from longitudinal studies with sufficient patient numbers in the HAART era. The proposed studies will utilize a continually expanding DREXELMED HIV- 1-infected patient cohort for cross-population and longitudinal studies for sequencing and structure/function analyses to examine the working hypothesis that binding site signatures within the LTR and viral envelope can be used as molecular markers to identify HIV-1-infected individuals more prone to developing advanced stage disease with end-organ involvement that may be exacerbated by specific co-morbidities such as cocaine or cannabinoid abuse The specific aims of this application are to continue to: (1) construct a HIV-1 (subtype B) LTR and Env polymerase chain reaction (PCR) product sequence database and clone bank derived from peripheral blood mononuclear cells (PBMCs) from HIV-1-infected peripheral blood (PB) collected longitudinally from patients with comprehensive clinical histories with respect to social and clinical demographics (initial and all return visits), (2) identify LTR and Env single nucleotide polymorphisms (SNPs) and co-selected SNPs (csSNPs) detected in LTRs derived from PBMCs [and, in selected circumstances, purified PB sub-populations, plasma virus, CNS tissues (NNTC) and other cellular compartments] obtained from a large well studied HIV-1- infected cohort using bioinformatic tools to examine SNPs at any of the 634 nucleotides of the HIV-1 LTR, within the HIV-1 gp120, or within the HIV-1 gp41, (3) construct a parallel PCR product sequence database and define specific LTR and Env SNPs and csSNPs from brain tissues with varying degrees of HIV-1-associated neurologic disorders obtained from the National Neuro-AIDS Tissue Consortium (NNTC)], and (4) determine the ability of HIV-1 LTR clones containing specific csSNPs to support transcription and viral replication studies.
PUBLIC HEALTH RELEVANCE: The proposal represents a significant and innovative approach involving the use of specific LTR and Env signature sequences to predict and track HIV-1 disease progression, the development of HIV-associated neurocognitive disorders, study the impact of substance abuse (cocaine and cannabinoids) on these processes, and potentially help guide the therapeutic management of HIV disease. The studies will also identify co-selected genetic elements within and between the HIV-1 LTR and Env that are associated with cell type-specific entry and control of viral gene expression and likely involved in viral pathogenesis and HIV disease.
描述(由申请人提供):人类免疫缺陷病毒1型(HIV-1)感染免疫系统、大脑和其他终末器官后的发病机制和疾病进展依赖于病毒在这些隔室内特定细胞群中的进入和复制,这些隔室通过各种直接和/或间接机制导致细胞功能障碍或死亡。这些病毒-宿主相互作用可受多种因素调节,包括病毒结合和进入、宿主细胞增殖和激活、细胞分化、抗逆转录病毒治疗状态、滥用物质,以及病毒和细胞蛋白与长末端重复序列(LTR)和相互作用以调节病毒表达的作用。HIV-1的复制能力进一步受到病毒准种进化的影响。研究表明,LTR内自然发生的序列变异会影响病毒启动子通过改变与细胞和病毒反式激活子的功能相互作用来驱动病毒表达的能力。最近的研究表明,HIV-1基因组内的遗传改变可能与HIV-1疾病的阶段、神经系统状态和/或器官区隔相关。然而,这些研究中有许多涉及对HAART前时代少数患者临床样本的交叉人群分析,而不是在HAART时代对足够数量的患者进行纵向研究。拟议的研究将利用不断扩大的DREXELMED HIV-1感染患者队列进行跨人群和纵向研究,进行测序和结构/功能分析,以检验LTR和病毒包膜内的结合位点特征可作为分子标记物,以识别更容易发展为终末器官受累的晚期疾病的HIV-1感染个体,这些疾病可能因特定合并症而加剧本申请的具体目的是继续:(1)构建HIV-1 (B亚型)LTR和Env聚合酶链反应(PCR)产物序列数据库和克隆库,该数据库来源于纵向采集的HIV-1感染外周血(PB)的单个核细胞(PBMCs),这些患者具有全面的临床病史,包括社会和临床人口统计学(首次和所有复诊);(2)鉴定LTR和Env单核苷酸多态性(snp)和共选择snp (cssnp),这些snp检测来自PBMCs[在选定的情况下,纯化的PB亚群,血浆病毒,CNS组织(NNTC)和其他细胞区室]的LTR,使用生物信息学工具检测HIV-1 LTR的634个核苷酸中的任何一个,在HIV-1 gp120内,或在HIV-1 gp41内。(3)构建平行PCR产物序列数据库,从国家神经艾滋病组织联合会(NNTC)获得的不同程度HIV-1相关神经疾病脑组织中定义特异性LTR和Env snp和cssnp;(4)确定含有特异性cssnp的HIV-1 LTR克隆支持转录和病毒复制研究的能力。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Brian Wigdahl其他文献
Brian Wigdahl的其他文献
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{{ truncateString('Brian Wigdahl', 18)}}的其他基金
Clinical and Translational Research Support Core for Institution # 269291
机构的临床和转化研究支持核心
- 批准号:
10475408 - 财政年份:2011
- 资助金额:
$ 67.08万 - 项目类别:
Clinical and Translational Research Support Core for Institution # 269291
机构的临床和转化研究支持核心
- 批准号:
10615179 - 财政年份:2011
- 资助金额:
$ 67.08万 - 项目类别:
Anti-HIV-1 activity of single & multicomponent biguanide
单抗HIV-1活性
- 批准号:
6809137 - 财政年份:2004
- 资助金额:
$ 67.08万 - 项目类别:
Co-evolution of HIV-1 Regulators in CNS Disease
HIV-1 调节因子在中枢神经系统疾病中的共同进化
- 批准号:
7067545 - 财政年份:2004
- 资助金额:
$ 67.08万 - 项目类别:
Co-evolution of HIV-1 Regulators in CNS Disease
HIV-1 调节因子在中枢神经系统疾病中的共同进化
- 批准号:
7849124 - 财政年份:2004
- 资助金额:
$ 67.08万 - 项目类别:
High Specificity HIV-1 Markers Predictive of Neuro-AIDS
预测神经艾滋病的高特异性 HIV-1 标记物
- 批准号:
6954088 - 财政年份:2004
- 资助金额:
$ 67.08万 - 项目类别:
Co-evolution of HIV-1 Regulators in CNS Disease
HIV-1 调节因子在中枢神经系统疾病中的共同进化
- 批准号:
6884008 - 财政年份:2004
- 资助金额:
$ 67.08万 - 项目类别:
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