Molecular Interactions of HIV-1 with the Nuclear Pore Complex
HIV-1 与核孔复合物的分子相互作用
基本信息
- 批准号:10241258
- 负责人:
- 金额:$ 136.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-01 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdoptedAntiviral TherapyArchitectureBindingBiologicalBiological AssayBiologyBiotinylationCaliberCapsidCapsid ProteinsCell NucleusCellsChemicalsComplexComputer ModelsConeCryo-electron tomographyCryoelectron MicroscopyDNADataDevelopmentDimerizationDockingElectron MicroscopyEngineeringEventEvolutionFactor VFluorescenceFullerenesFutureGap JunctionsGene ExpressionGenomeHIVHIV-1ImageInfectionIntegration Host FactorsInterphase CellIonsKaryopherinsKnowledgeLabelLengthLightLiteratureMediatingMethodsMolecularMolecular StructureMonitorNuclearNuclear EnvelopeNuclear ImportNuclear PoreNuclear Pore ComplexNuclear Pore Complex ProteinsPathway interactionsPenetrationPeroxidasesPhytic AcidProcessProteinsProteomicsProtocols documentationReportingResearchReverse TranscriptionStructureSystemTechniquesViralViral GenesVirusVirus IntegrationVirus ReplicationVisualizationanalogascorbatebasecrosslinkdesignexperimental studyimaging approachinnovationinsightintegration siteknock-downmacromoleculemultidisciplinarynew therapeutic targetnovelnovel strategiesnovel virusnucleocytoplasmic transportparticlepassive transportpleiotropismpreventviral DNA
项目摘要
HIV-1 enters the nucleus of non-dividing cells where the reverse transcribed viral DNA is
integrated into the host genome. Whereas the nuclear pore complex (NPC) prevents passive
transport of large macromolecules, HIV-1 has evolved effective strategies to penetrate this barrier.
The HIV-1 nuclear import is a poorly understood process that involves complex interactions with
the nuclear import machinery, including several nucleoporins, transportin-3, and CPSF6, all of
which bind the viral capsid core, which comprises hundreds of copies of the capsid protein (CA).
Pleiotropic effects caused by nucleoporin knockdown and the ability of HIV-1 to use alternative
import pathways have impeded the mechanistic studies of nuclear import and frustrated efforts to
identify the full array of host factors involved in this process. Our single particle tracking
experiments revealed that HIV-1 infection progresses through CA-dependent docking at the
nuclear membrane, followed by uncoating (loss of CA) and CA-dependent nuclear transport to
the sites of integration. However, very little is known regarding the molecular details and dynamics
of virus-NPC interactions, including the structural changes in the architecture of both HIV-1 and
the NPC in the course of nuclear import. There is thus an unmet need for structural and functional
studies on the molecular mechanisms of HIV-1 nuclear import in the context of productive
infection. We propose to combine cutting-edge approaches developed by our highly collaborative
team to delineate the molecular interactions and structural changes in the virus and NPC during
the nuclear import. Specifically, we will: (1) identify the host factors involved in HIV-1 import using
novel proteomics and chemical cross-linking approaches; (2) obtain cryo-electron tomography
(cryo-ET) and cross-linking mass-spec structures of the HIV-1 core/NPC complexes by capturing
the incoming virus through our new on-demand pore clogging assay; and (3) develop correlative
fluorescence/cryo-ET imaging pipeline to structurally characterize the intermediates of HIV-1
nuclear import. Knowledge of molecular interactions during the HIV-1 nuclear import should help
identify novel therapeutic targets to block infection, provide a framework for studies of the nuclear
import of other viruses and further fundamental understanding of the nuclear pore function.
HIV-1进入非分裂细胞的细胞核,那里有逆转录的病毒DNA
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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Gregory B Melikian其他文献
Gregory B Melikian的其他文献
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{{ truncateString('Gregory B Melikian', 18)}}的其他基金
Molecular Interactions of HIV-1 with the Nuclear Pore Complex
HIV-1 与核孔复合物的分子相互作用
- 批准号:
10462620 - 财政年份:2019
- 资助金额:
$ 136.92万 - 项目类别:
Inhibition of viral entry by interferon-induced proteins
干扰素诱导蛋白抑制病毒进入
- 批准号:
10418696 - 财政年份:2018
- 资助金额:
$ 136.92万 - 项目类别:
Inhibition of viral entry by interferon-induced proteins
干扰素诱导蛋白抑制病毒进入
- 批准号:
10190798 - 财政年份:2018
- 资助金额:
$ 136.92万 - 项目类别:
Imaging of Single HIV-1 Uncoating and Transport to the nucleus
单个 HIV-1 脱壳和转运至细胞核的成像
- 批准号:
9354023 - 财政年份:2017
- 资助金额:
$ 136.92万 - 项目类别:
Functional Characterization of the Hepatitis C Virus E1-E2 Glycoproteins
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7522862 - 财政年份:2009
- 资助金额:
$ 136.92万 - 项目类别:
Functional Characterization of the Hepatitis C Virus E1-E2 Glycoproteins
丙型肝炎病毒 E1-E2 糖蛋白的功能表征
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8116923 - 财政年份:2009
- 资助金额:
$ 136.92万 - 项目类别:
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