Mechanisms that determine subcellular sites of HIV-1 assembly
决定 HIV-1 组装亚细胞位点的机制
基本信息
- 批准号:8013495
- 负责人:
- 金额:$ 32.32万
- 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:2007-02-01 至 2012-04-30
- 项目状态:已结题
- 来源:
- 关键词:AccountingAddressAffectAmino Acid SubstitutionAmino AcidsAnti-HIV AgentsAntiviral AgentsBindingBinding ProteinsBiological AssayCell membraneCellsClone CellsCoupledDataDefectDependenceDevelopmentDrug Delivery SystemsEnzymesFactor AnalysisFluorescence MicroscopyFutureGaggingGoalsHIV-1Hela CellsIn VitroInfectionInterventionLeadLipid BindingLipidsLiposomesLocationMeasurementMediatingMembraneMembrane LipidsMolecularMultivesicular BodyPathway interactionsPhosphatidylinositol PhosphatesPhosphatidylinositolsPhospholipidsPhosphoric Monoester HydrolasesPlayProcessProductionProteinsRecyclingReportingResearch ProposalsResistanceRoleSeriesSiteSystemT-LymphocyteTertiary Protein StructureTestingTranslationsTransmembrane TransportVesicleViralViral Structural ProteinsVirionVirusVirus AssemblyVirus-like particlebasecell typegenetic regulatory proteininstrumentlate endosomemacrophagemutantoverexpressionparticleprotein transportresearch studytrafficking
项目摘要
DESCRIPTION (provided by applicant): HIV-1 particle production, a process driven by the viral structural protein Gag, takes place predominantly at the plasma membrane in cell types including T cells, whereas in macrophages a majority of virus particles appears to assemble in the late endosomes. The molecular mechanisms that determine the sites of virus assembly remain to be elucidated. The observed cell type difference is consistent with the possibility that a cellular factor(s) is involved in determining the subcellular location of HIV-1 assembly. We recently reported that depletion of the plasma membrane lipid PI(4,5)P2 in HeLa cells relocates Gag from the plasma membrane to late endosomes and markedly reduces virus particle production. Preliminary results show that Gag binding to total membrane is also impaired upon PI(4,5)P2 depletion. Recent structural data suggest that PI(4,5)P2 interacts directly with the matrix domain of Gag. These results suggest that a Gag-PI(4,5)P2 interaction is essential for virus assembly at the plasma membrane. Our goal in this proposal is to elucidate the molecular mechanisms by which PI(4,5)P2 regulates HIV-1 assembly in different cell types. Our specific aims are: [Aim 1] To identify Gag regions that are responsible for PI(4,5)P2 dependence. This will be achieved by a) characterization of Gag derivatives and b) isolation and characterization of viruses adapted to low PI(4,5)P2 levels. [Aim 2] To determine if PI(4,5)P2 regulates Gag localization by directly binding to Gag or through a PI(4,5)P2-dependent cellular trafficking pathway, or both. To address the first possibility, we will develop in vitro Gag-lipid binding assays. To examine the second possibility, we will analyze the impact of inhibition of membrane transport pathways and compare it with the effects of cellular PI(4,5)P2 depletion. [Aim 3] To examine, the role of PI(4,5)P2 in Gag localization to late endosomes and virus particle production in macrophages. We will perform quantitative analyses of PI(4,5)P2-Gag colocalization and virus release from macrophages with or without PI(4,5)P2 perturbation. The subcellular sites of virus assembly play key roles in the efficiency of virus production and viral persistence. Therefore, analyses of factors that determine the assembly sites have major implications in strategies for intervention in HIV-1 infection. The experiments proposed here will determine the roles played by PI(4,5)P2 in HIV-1 particle production and will contribute to the future development of antiviral drugs that target HIV-1 assembly and release.
描述(由申请人提供):HIV-1 颗粒的产生是由病毒结构蛋白 Gag 驱动的过程,主要发生在包括 T 细胞在内的细胞类型的质膜上,而在巨噬细胞中,大多数病毒颗粒似乎在晚期内体。决定病毒组装位点的分子机制仍有待阐明。观察到的细胞类型差异与细胞因子参与确定 HIV-1 组装的亚细胞位置的可能性一致。我们最近报道,HeLa 细胞中质膜脂质 PI(4,5)P2 的消耗使 Gag 从质膜转移到晚期内体,并显着减少病毒颗粒的产生。初步结果表明,Gag 与总膜的结合也会因 PI(4,5)P2 耗尽而受损。最近的结构数据表明 PI(4,5)P2 直接与 Gag 的基质域相互作用。这些结果表明 Gag-PI(4,5)P2 相互作用对于病毒在质膜上的组装至关重要。我们本提案的目标是阐明 PI(4,5)P2 在不同细胞类型中调节 HIV-1 组装的分子机制。我们的具体目标是: [目标 1] 确定负责 PI(4,5)P2 依赖性的 Gag 区域。这将通过 a) Gag 衍生物的表征和 b) 适应低 PI(4,5)P2 水平的病毒的分离和表征来实现。 [目标 2] 确定 PI(4,5)P2 是否通过直接结合 Gag 或通过 PI(4,5)P2 依赖性细胞运输途径或两者来调节 Gag 定位。为了解决第一种可能性,我们将开发体外 Gag-脂质结合测定法。为了检验第二种可能性,我们将分析膜转运途径抑制的影响,并将其与细胞 PI(4,5)P2 耗竭的影响进行比较。 [目标 3] 研究 PI(4,5)P2 在 Gag 定位到晚期内体和巨噬细胞中病毒颗粒产生中的作用。我们将在有或没有 PI(4,5)P2 扰动的情况下对 PI(4,5)P2-Gag 共定位和巨噬细胞释放病毒进行定量分析。病毒组装的亚细胞位点在病毒生产效率和病毒持久性方面发挥着关键作用。因此,对决定装配位点的因素进行分析对于干预 HIV-1 感染的策略具有重大意义。这里提出的实验将确定 PI(4,5)P2 在 HIV-1 颗粒产生中所发挥的作用,并将有助于未来开发针对 HIV-1 组装和释放的抗病毒药物。
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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Akira Ono其他文献
Akira Ono的其他文献
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{{ truncateString('Akira Ono', 18)}}的其他基金
Mechanisms that determine subcellular sites of HIV-1 assembly
决定 HIV-1 组装亚细胞位点的机制
- 批准号:
10617799 - 财政年份:2022
- 资助金额:
$ 32.32万 - 项目类别:
Mechanisms that determine subcellular sites of HIV-1 assembly
决定 HIV-1 组装亚细胞位点的机制
- 批准号:
10362907 - 财政年份:2022
- 资助金额:
$ 32.32万 - 项目类别:
Effects of lymphoid tissue stromal cells on cell-to-cell HIV-1 spread
淋巴组织基质细胞对细胞间 HIV-1 传播的影响
- 批准号:
9090035 - 财政年份:2015
- 资助金额:
$ 32.32万 - 项目类别:
Recruitment of BST-2/tetherin to HIV-1 assembly sites
将 BST-2/tetherin 招募到 HIV-1 装配位点
- 批准号:
8291214 - 财政年份:2011
- 资助金额:
$ 32.32万 - 项目类别:
Recruitment of BST-2/tetherin to HIV-1 assembly sites
将 BST-2/tetherin 招募到 HIV-1 装配位点
- 批准号:
8210153 - 财政年份:2011
- 资助金额:
$ 32.32万 - 项目类别:
Relationships between HIV-1 assembly and the plasma membrane organization
HIV-1组装与质膜组织之间的关系
- 批准号:
8138123 - 财政年份:2010
- 资助金额:
$ 32.32万 - 项目类别:
Mechanisms that determine subcellular sites of HIV-1 assembly
决定 HIV-1 组装亚细胞位点的机制
- 批准号:
8068079 - 财政年份:2010
- 资助金额:
$ 32.32万 - 项目类别:
Mechanisms that determine subcellular sites of HIV-1 assembly
决定 HIV-1 组装亚细胞位点的机制
- 批准号:
10203782 - 财政年份:2007
- 资助金额:
$ 32.32万 - 项目类别:
Mechanisms that determine subcellular sites of HIV-1 assembly
决定 HIV-1 组装亚细胞位点的机制
- 批准号:
7350922 - 财政年份:2007
- 资助金额:
$ 32.32万 - 项目类别:
Mechanisms that determine subcellular sites of HIV-1 assembly
决定 HIV-1 组装亚细胞位点的机制
- 批准号:
8822791 - 财政年份:2007
- 资助金额:
$ 32.32万 - 项目类别:
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