Imaging early steps of HIV-1 infection and virus-host factor interactions
HIV-1 感染的早期成像和病毒-宿主因子相互作用
基本信息
- 批准号:10548587
- 负责人:
- 金额:$ 58.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-06-17 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:Amino AcidsAntiviral AgentsBindingBiochemicalBiochemistryBiological AssayBiophysicsCapsidCapsid ProteinsCell NucleusCell fusionCellsComplexConflict (Psychology)CytoplasmDNADNA IntegrationDataDyesElectron MicroscopyEventGenesGenetic TranscriptionGenomeHIVHIV-1ImageImaging DeviceImaging TechniquesImaging technologyIn VitroInfectionInnate Immune ResponseIntegraseIntegration Host FactorsKnowledgeLabelLightLocationMacromolecular ComplexesMapsMass Spectrum AnalysisMicroscopyModelingNuclearNuclear ImportNuclear PorePermeabilityProcessProteinsRecombinantsRegulationReportingReverse TranscriptionRibonucleoproteinsRoleSiteTechniquesTechnologyTravelTubeValidationViralVirusVisualizationbaseexperimental studyintegration siteknock-downlive cell imagingminimally invasivenovelnovel strategiesnovel virusnucleocytoplasmic transportrecruitstemstructural biologytranscriptional coactivator p75viral DNAviral RNAvirology
项目摘要
Key steps of early HIV-1 infection include reverse transcription, nuclear import of replication complexes and
transport to nuclear speckles followed by viral DNA integration into host genome. At some point before
integration, the capsid shell surrounding the viral ribonucleoprotein complex must disassemble (uncoat) to
release the viral pre-integration complexes. It is currently unclear where in the cell uncoating occurs and whether
the capsid (CA) protein is progressively or synchronously lost from the capsid shell, yet optimal core stability is
essential for evading the host innate immune responses and for nuclear import of functional viral complexes.
Highly divergent findings regarding HIV-1 uncoating have been reported by several groups based upon the
visualization of single virus uncoating in live cells. These conflicting results stem, in part, from the use of indirect
CA labeling approaches and lack of minimally invasive direct fluorescent labeling of HIV-1 capsid. We
hypothesize that HIV-1 uncoating is a multi-step process that involves permeabilization of the capsid shell in the
cytoplasm, remodeling at the nuclear pore, and loss of CA in the nucleus. We will use a novel minimally invasive
direct CA labeling strategy, which is based on site-directed incorporation of non-canonical amino acids and click-
labeling with an organic dye, to elucidate single HIV-1 core permeabilization and uncoating events resulting to
infection (Aim 1). Another gap in knowledge pertains to post-uncoating processes leading to HIV-1 integration
and sub-nuclear compartments where integration occurs. We hypothesize that the viral pre-integration complex
separates from the capsid shell and travels to the edge of a nuclear speckle where it engages the integrase-
binding host factor LEDGF/p75 for integration into host genome. We will employ a novel live-cell single viral DNA
visualization technology to track nuclear transport and productive integration of single viral complexes that
establish actively transcribing viral RNA foci (Aim 2). Finally, we will use a powerful panel of biochemical,
biophysical, structural biology, virology, and microscopy techniques to characterize a novel HIV-1 CA binding
host factor, RBM14, which we hypothesize to modulate pre-integration steps of infection after nuclear import
(Aim 3). These experiments are expected to elucidate the controversial HIV-1 uncoating process, reveal the
dynamic events leading to productive integration and sites of integration, as well as delineate the role of RBM14-
capsid interactions in early infection, thus informing novel antiviral strategies.
早期HIV-1感染的关键步骤包括逆转录、复制复合物的核输入和
转运到核斑点,随后病毒DNA整合到宿主基因组中。在之前的某个时候
整合时,病毒核糖核蛋白复合物周围的衣壳必须分解(脱壳),
释放病毒整合前复合物目前尚不清楚细胞中的何处发生脱膜,以及
衣壳(CA)蛋白逐渐或同步地从衣壳壳中丢失,但最佳的核心稳定性是
对于逃避宿主先天免疫应答和功能性病毒复合物的核输入是必需的。
几个研究小组报告了关于HIV-1脱壳的高度分歧的发现,
活细胞中单个病毒脱壳的可视化。这些相互矛盾的结果部分源于使用间接
CA标记方法和缺乏HIV-1衣壳的微创直接荧光标记。我们
假设HIV-1去包被是一个多步骤的过程,包括在细胞膜中衣壳壳的透化,
细胞质中,在核孔的重塑,和CA在细胞核中的损失。我们将使用一种新的微创
直接CA标记策略,其基于非典型氨基酸的定点掺入和点击,
用有机染料标记,以阐明单个HIV-1核心透化和去包被事件,
感染(目标1)。另一个知识空白涉及到导致HIV-1整合的去包被后过程
以及整合发生的亚核区室。我们假设病毒整合前复合体
从衣壳壳分离,并移动到核斑点的边缘,在那里它与整合酶结合,
结合宿主因子LEDGF/p75以整合到宿主基因组中。我们将采用一种新的活细胞单病毒DNA
可视化技术来跟踪单个病毒复合物的核运输和生产性整合,
建立活跃转录的病毒RNA灶(Aim 2)。最后,我们将使用一个强大的生化小组,
生物物理学、结构生物学、病毒学和显微镜技术来表征一种新的HIV-1 CA结合
宿主因子RBM 14,我们假设其调节核输入后感染的整合前步骤
(Aim 3)。这些实验有望阐明有争议的HIV-1脱壳过程,揭示
导致生产性一体化的动态事件和一体化地点,并说明成果管理制的作用14-
衣壳相互作用在早期感染,从而通知新的抗病毒策略。
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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Mamuka Kvaratskhelia其他文献
Mamuka Kvaratskhelia的其他文献
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{{ truncateString('Mamuka Kvaratskhelia', 18)}}的其他基金
Imaging early steps of HIV-1 infection and virus-host factor interactions
HIV-1 感染的早期成像和病毒-宿主因子相互作用
- 批准号:
10646359 - 财政年份:2022
- 资助金额:
$ 58.21万 - 项目类别:
Core B: Proteomics and Protein Analysis Core
核心 B:蛋白质组学和蛋白质分析核心
- 批准号:
8742037 - 财政年份:2014
- 资助金额:
$ 58.21万 - 项目类别:
Cellular Cofactors of Murine Leukemia Virus Integrase
鼠白血病病毒整合酶的细胞辅因子
- 批准号:
8709737 - 财政年份:2014
- 资助金额:
$ 58.21万 - 项目类别:
Cellular Cofactors of Murine Leukemia Virus Integrase
鼠白血病病毒整合酶的细胞辅因子
- 批准号:
8797297 - 财政年份:2014
- 资助金额:
$ 58.21万 - 项目类别:
Structural determinants for integrase pleiotropism in viral maturation
病毒成熟过程中整合酶多效性的结构决定因素
- 批准号:
10363022 - 财政年份:2012
- 资助金额:
$ 58.21万 - 项目类别:
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