Bioinformatic Mapping of HIV-1 Nef Manipulation of T-Cell Activation and Function
HIV-1 Nef 操纵 T 细胞激活和功能的生物信息学图谱
基本信息
- 批准号:7433916
- 负责人:
- 金额:$ 11.33万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-06-15 至 2010-05-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAdoptedAdultAllelesBioinformaticsBiologicalBiostatistical MethodsCD28 geneCD4 Positive T LymphocytesCD8B1 geneCell Differentiation processCell MaturationCell physiologyCell surfaceCellsCharacteristicsClassClinicalClinical VirologyCollaborationsDataDendritic CellsDevelopmentDiseaseDisease OutcomeEffectivenessEnvironmentEpitopesEvolutionFlow CytometryGeneral HospitalsGeneticGenetic DeterminismGenetic VariationGenomeGoalsGrantHIVHIV vaccineHIV-1HumanImmuneImmune systemImmunologyImmunophenotypingImmunotherapeutic agentImpairmentIn VitroInfectionInterleukin-2LaboratoriesLaboratory MarkersLongitudinal StudiesLymphocyte-Specific p56LCK Tyrosine Protein KinaseMAPK14 geneMapsMeasuresOutcomeParticipantPathway interactionsPatientsPatternPersonal SatisfactionPersonsPhenotypePhosphorylationPopulationPositioning AttributeProtein RegionProteinsQualifyingReportingResearchRoleSCID-hu MiceSIVSan FranciscoSignal PathwaySignal TransductionSignaling ProteinSiteSpecimenStimulusStructureSurfaceT-Cell ActivationT-Cell ReceptorT-LymphocyteTimeTreesVariantViralVirulenceVirulence FactorsVirulentWorkbaseclinical phenotypecohortcytokinedesignfallsimprovedin vivokillingsloss of functionmouse modelnef Genesnef Proteinp65perforinpressurereceptorresponsetherapy developmenttoolvaccination strategyvirus genetics
项目摘要
DESCRIPTION (provided by applicant): HIV disease is characterized by high level CD8+ T cell activation and impairment in T cell function. Despite being the distinguishing characteristic of HIV-1 infection, the basis for the variation in CD8+ T cell activation in humans is not well understood. Variation in circulating strains of HIV-1 may account for this variation. We intend to map viral genetic determinants of T cell activation within the HIV-1 Nef protein. The HIV-1 Nef protein has been repeatedly implicated in manipulation of the human immune system. Adopting a very wide array of functions, HIV-1 Nef down modulates expression of key surface receptors, such as CD4, CD28, and MHC, facilitates viral entry and release, directly interacts with signaling proteins, such as the T cell receptor proximal kinase, Lck, and induce IL-2 expression. The sites c
onferring these functions to Nef fall in distinct regions of the protein - regions which vary in sequence across HIV-1 strains. Nef is expressed early in infection, and is a target for CTL immune escape. HIV-1 Nef activity within infected CD4+ T cells influences cellular response to stimuli, cytokine secretion patterns, and interaction with CD8+ T cells. In this way, Nef may influence CD8+ T cell activation levels and T cell maturation. While Nef has been studied extensively in vitro, the impact of Nef sequence variation in vivo has not been well studied. We propose to relate HIV-1 viral nef sequence to T cell activation levels, T cell phenotype, and T cell signaling alterations by use of advanced bioinformatic mapping tools. We will perform these studies in a cohort of 220 recently HIV-1 infected adults with well-characterized disease course and in collaboration with the UCSF/CFAR Core Immunology Laboratory and the UCSF Laboratory of Clinical Virology. We will use tree- structured biostatistical methods and their extensions which are well suited to handling of high-dimensional biological data types, such as genetic sequence and flow cytometry. The strengths of this application include the availability of specimens from a well-characterized cohort of HIV-1 infected adults; the use of advanced bioinformatic mapping tools; high-dimensional flow cytometric measures of function and signaling; a highly qualified inter-disciplinary research team; and a longitudinal approach to study of a genetically diverse entity, HIV-1. This work will facilitate development of therapies to improve the effectiveness of T cell responses and design of an effective HIV vaccine. HIV disease is characterized by high level CD8+ T cell activation and impairment in T cell function. Despite being the distinguishing characteristic of HIV-1 infection, the basis for the variation in CD8+ T cell activation in humans is not well understood. Variation in circulating strains of HIV-1 may account for this variation. We intend to map viral genetic determinants of T cell activation within the HIV-1 Nef protein.
描述(由申请人提供):HIV疾病的特征是CD8+ T细胞高水平活化和T细胞功能受损。尽管这是HIV-1感染的显著特征,但人类CD8+ T细胞活化变异的基础尚不清楚。HIV-1流行毒株的变异可能解释了这种变异。我们打算在HIV-1 Nef蛋白内绘制T细胞活化的病毒遗传决定因素。HIV-1 Nef蛋白多次被认为与人体免疫系统的操纵有关。HIV-1 Nef具有非常广泛的功能,下调关键表面受体(如CD4、CD28和MHC)的表达,促进病毒进入和释放,直接与信号蛋白(如T细胞受体近端激酶Lck)相互作用,诱导IL-2表达。网站c
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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Jason David Barbour其他文献
Jason David Barbour的其他文献
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{{ truncateString('Jason David Barbour', 18)}}的其他基金
Decryption of KIR genetics and function in early HIV-1 infection
解密早期 HIV-1 感染中的 KIR 遗传学和功能
- 批准号:
8204799 - 财政年份:2009
- 资助金额:
$ 11.33万 - 项目类别:
Decryption of KIR genetics and function in early HIV-1 infection
解密早期 HIV-1 感染中的 KIR 遗传学和功能
- 批准号:
7751273 - 财政年份:2009
- 资助金额:
$ 11.33万 - 项目类别:
Decryption of KIR genetics and function in early HIV-1 infection
解密早期 HIV-1 感染中的 KIR 遗传学和功能
- 批准号:
8417022 - 财政年份:2009
- 资助金额:
$ 11.33万 - 项目类别:
Decryption of KIR genetics and function in early HIV-1 infection
解密早期 HIV-1 感染中的 KIR 遗传学和功能
- 批准号:
8236131 - 财政年份:2009
- 资助金额:
$ 11.33万 - 项目类别:
Decryption of KIR genetics and function in early HIV-1 infection
解密早期 HIV-1 感染中的 KIR 遗传学和功能
- 批准号:
7620730 - 财政年份:2009
- 资助金额:
$ 11.33万 - 项目类别:
Decryption of KIR genetics and function in early HIV-1 infection
解密早期 HIV-1 感染中的 KIR 遗传学和功能
- 批准号:
8011425 - 财政年份:2009
- 资助金额:
$ 11.33万 - 项目类别:
Bioinformatic Mapping of HIV-1 Nef Manipulation of T-Cell Activation and Function
HIV-1 Nef 操纵 T 细胞激活和功能的生物信息学图谱
- 批准号:
7336749 - 财政年份:2007
- 资助金额:
$ 11.33万 - 项目类别:
Variation in Immune Activation in HIV-1 Infected Persons
HIV-1 感染者免疫激活的变化
- 批准号:
7240428 - 财政年份:2005
- 资助金额:
$ 11.33万 - 项目类别:
Variation in Immune Activation in HIV-1 Infected Persons
HIV-1 感染者免疫激活的变化
- 批准号:
7086886 - 财政年份:2005
- 资助金额:
$ 11.33万 - 项目类别:
Variation in Immune Activation in HIV-1 Infected Persons
HIV-1 感染者免疫激活的变化
- 批准号:
7431779 - 财政年份:2005
- 资助金额:
$ 11.33万 - 项目类别:
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