Mechanism and role of nuclear entry in HIV-1 replication
HIV-1复制中核进入的机制和作用
基本信息
- 批准号:8449072
- 负责人:
- 金额:$ 41.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-04-01 至 2017-03-31
- 项目状态:已结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeAddressAffectAnimal ModelAnti-Retroviral AgentsAntiviral AgentsBiological ProcessCD4 Positive T LymphocytesCapsidCapsid ProteinsCell NucleusCellsComplexDataDependenceDevelopmentDrug TargetingEscape MutantEventEvolutionGeneticGoalsHIV-1HLA-B27 AntigenInfectionIntegration Host FactorsInterphase CellIntracellular TransportLife Cycle StagesLinkMacacaModelingMolecularMutationNuclearPathogenesisPathway interactionsPatientsPlayPropertyRecurrenceResearchRestRoleSIVTestingTissuesViralViral PathogenesisViruscell typeflexibilityin vivoinsightmacrophagemutantnovelnovel therapeuticsnucleocytoplasmic transportpressureresponsetransmission processviral DNA
项目摘要
DESCRIPTION (provided by applicant): The ability of HIV-1 to utilize the cellular machinery for nuclear entry allows the virus to infect resting CD4+ T cells and tissue macrophages, the two non-dividing cell types believed to play critical roles in HIV-1 transmission, persistence and pathogenesis. However, the precise mechanism and specific requirement of nuclear entry in HIV-1 replication remains unclear. Capsid is the major determinant for HIV-1 infection of non-dividing cells but also dictates the dependence of HIV-1 on TNPO3, a host molecule recently implicated in HIV-1 nuclear entry. Our preliminary studies found a perfect correlation between the dependence of HIV-1 capsid mutants on TNPO3 and their ability to infect non-dividing cells. The hypothesis being tested in this project is that the capsid protein regulates HIV-1 nuclear entry by assisting intracellular virus complexes in hijacking the TNPO3-dependent cellular machinery and this ability is critical for HIV-1 replication in vivo. In Aim 1, we will determine hw the HIV-1 capsid protein determines TNPO3 usage by HIV-1 and how TNPO3 and other host factors promote HIV-1 nuclear entry. We will next define the specific requirement of this TNPO3-dependent nuclear entry for HIV-1 replication in vivo. In Aim 2, we will study a unique case of HIV-1 capsid evolution in patients carrying the HLA-B27. Preliminary data suggests recurrent selection of TNPO3- dependent viruses in these patients. In Aim 3, we will combine our genetic data with a well-studied macaque model of HIV-1 by using simian immunodeficiency virus (SIV) to directly address the importance of nuclear entry in vivo. Here we will generate and utilize TNPO3-independent SIV mutants, which either retain or lose the ability to infect non-dividing cells. Successful completion of this proposed research will help us understand the mechanism by which HIV-1 exploits the nuclear transport machinery to maximize its propagation.
描述(由申请人提供):HIV-1利用细胞机制进入核的能力使病毒能够感染静止的CD4+T细胞和组织巨噬细胞,这两种不分裂的细胞类型被认为在HIV-1的传播、持久性和发病机制中发挥关键作用。然而,HIV-1复制过程中核进入的确切机制和具体要求仍不清楚。衣壳是HIV-1感染未分裂细胞的主要决定因素,但也决定了HIV-1对TNPO3的依赖性,TNPO3是最近与HIV-1核进入有关的宿主分子。我们的初步研究发现,HIV-1衣壳突变体对TNPO3的依赖性与它们感染未分裂细胞的能力之间存在完美的相关性。本项目验证的假设是,衣壳蛋白通过协助细胞内病毒复合体劫持依赖TNPO3的细胞机制来调节HIV-1的核进入,这一能力对HIV-1在体内的复制至关重要。在目标1中,我们将确定HIV-1衣壳蛋白决定HIV-1对TNPO3的利用,以及TNPO3和其他宿主因素如何促进HIV-1核进入。接下来,我们将定义这种依赖于TNPO3的核进入对HIV-1在体内复制的具体要求。在目标2中,我们将研究一例携带人类白细胞抗原B27的患者中HIV-1衣壳演变的独特案例。初步数据表明,这些患者反复选择依赖TNPO3的病毒。在目标3中,我们将通过使用猴免疫缺陷病毒(SIV)将我们的基因数据与HIV-1猕猴模型相结合,直接解决体内核进入的重要性。在这里,我们将产生和利用不依赖于TNPO3的SIV突变体,它们要么保留要么失去感染未分裂细胞的能力。这项拟议研究的成功完成将有助于我们了解艾滋病毒-1利用核运输机制最大限度地传播它的机制。
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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Masahiro Yamashita其他文献
Highly selective H2 or O2 sorption over N2 in metal-organic frame-work with dynamic aperture
在具有动态孔径的金属有机框架中对 N2 进行高选择性 H2 或 O2 吸附
- DOI:
- 发表时间:
2016 - 期刊:
- 影响因子:0
- 作者:
Shinya Takaishi;Bin Wu;Shin-ichiro Noro;Masahiro Yamashita - 通讯作者:
Masahiro Yamashita
シリル-NHCキレート配位子を持つイリジウム錯体の合成,構造および反応性
含硅烷基 NHC 螯合配体的铱配合物的合成、结构和反应活性
- DOI:
- 发表时间:
2019 - 期刊:
- 影响因子:0
- 作者:
Shinya Takaishi;Bin Wu;Shin-ichiro Noro;Masahiro Yamashita;桜庭 幹太,小室 貴士,飛田 博実 - 通讯作者:
桜庭 幹太,小室 貴士,飛田 博実
Masahiro Yamashita的其他文献
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{{ truncateString('Masahiro Yamashita', 18)}}的其他基金
Single-cell analysis of HIV-1 production and transmission
HIV-1 产生和传播的单细胞分析
- 批准号:
10086846 - 财政年份:2019
- 资助金额:
$ 41.88万 - 项目类别:
Single-cell analysis of HIV-1 production and transmission
HIV-1 产生和传播的单细胞分析
- 批准号:
9906849 - 财政年份:2019
- 资助金额:
$ 41.88万 - 项目类别:
Single-cell analysis of HIV-1 production and transmission
HIV-1 产生和传播的单细胞分析
- 批准号:
10132234 - 财政年份:2019
- 资助金额:
$ 41.88万 - 项目类别:
Single-cell analysis of HIV-1 production and transmission
HIV-1 产生和传播的单细胞分析
- 批准号:
10589935 - 财政年份:2019
- 资助金额:
$ 41.88万 - 项目类别:
Single-cell analysis of HIV-1 production and transmission
HIV-1 产生和传播的单细胞分析
- 批准号:
10375452 - 财政年份:2019
- 资助金额:
$ 41.88万 - 项目类别:
Mechanism and role of nuclear entry in HIV-1 replication
HIV-1复制中核进入的机制和作用
- 批准号:
8639465 - 财政年份:2012
- 资助金额:
$ 41.88万 - 项目类别:
Diverse Functions of HIV-1 Capsid During Postentry Events
HIV-1衣壳在进入后事件期间的多种功能
- 批准号:
10081224 - 财政年份:2012
- 资助金额:
$ 41.88万 - 项目类别:
Diverse Functions of HIV-1 Capsid During Postentry Events
HIV-1衣壳在进入后事件期间的多种功能
- 批准号:
9979730 - 财政年份:2012
- 资助金额:
$ 41.88万 - 项目类别:
Mechanism and role of nuclear entry in HIV-1 replication
HIV-1复制中核进入的机制和作用
- 批准号:
9031054 - 财政年份:2012
- 资助金额:
$ 41.88万 - 项目类别:
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