HIV-1 Vpu and BST-2/CD317
HIV-1 Vpu 和 BST-2/CD317
基本信息
- 批准号:8965996
- 负责人:
- 金额:$ 44.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-12-01 至 2018-11-30
- 项目状态:已结题
- 来源:
- 关键词:Antiviral ResponseCell membraneCellsComplexDataEnhancing AntibodiesEnvironmentGene ExpressionHIVHIV-1HealthHost DefenseHumanImmuneImmune responseImmunologic SurveillanceIndividualInfectionIntegral Membrane ProteinInterferon Type IInterferonsLearningMHC Class II GenesMediatingMolecularNF-kappa BPan GenusPrimate LentivirusesProteinsResearch PersonnelRoleSignal TransductionSiteStructure-Activity RelationshipTransmembrane DomainVariantViralViral AntigensViral GenesViral ProteinsVirionVirusVirus DiseasesVirus ReplicationWorkadaptive immunitybasecofactorcytotoxicityin vivoresponsesensortransmission processubiquitin ligasevpu Protein
项目摘要
DESCRIPTION (provided by applicant): HIV-1 encodes proteins that modulate the host cellular environment to optimize viral replication and avoid host defenses. The accessory protein Vpu accomplishes this in part by antagonizing the activity of the host protein BST2 (also known as HM1.24, CD317, and tetherin). BST2 is an interferon-inducible integral membrane protein. This protein is the restriction factor that Vpu counteracts to stimulate the release of virus particles (virions) from infected host cells. We and others have shown that BST2 directly holds nascent virions to the plasma membrane of infected cells; that Vpu counteracts this by removing BST2 from its site of action at the plasma membrane; that BST2 is upregulated in response to HIV replication in vivo; and that BST2 serves a signaling and virus-sensing function through the induction of NF-kB transcriptional activity. The latter finding fits an emerging paradigm in which retroviral restriction factors have multifaceted roles during the innate immune response. Moreover, the field has developed evidence that HIV-1 Vpu specifically adapted to acquire activity as an antagonist of BST2 upon transmission of SIVcpz from chimpanzees to humans. Several key questions now need to be answered, and these are the basis for the specific aims of the proposal: 1) what are the molecular determinants and topologies of the protein's restricting and signaling activities? 2) in addition to the TrCP containing ubiquitin ligase complex, what are the cellular cofactors that support the antagonism of BST2 and how does Vpu interact with them? 3) how does BST2 activate NF-¿B and detect viral gene expression? Does BST2 facilitate aspects of the adaptive immune response? And 4) does Vpu-mediated antagonism of BST2 contribute to HIV-1 transmission? Through the work proposed here, we expect to learn how the tethering and signaling functions of BST2 are structurally integrated; how Vpu modulates BST2 to antagonize restriction and signaling; the mechanisms by which BST2 signals and responds to viral gene expression and assembly; whether BST2 facilitates adaptive immunity; and whether any of the Vpu functions related to BST2 are optimized in HIV-1 variants that are transmitted between individuals. We expect to support or reject the notion that BST2-antagonism is an important aspect of HIV-1's ability to escape immune surveillance and establish a persistent infection in the human host.
描述(由申请人提供):HIV-1编码调节宿主细胞环境的蛋白质,以优化病毒复制并避免宿主防御。辅助蛋白Vpu部分通过拮抗宿主蛋白BST2(也称为HM1.24、CD317和tetherin)的活性来实现这一功能。BST2是一种干扰素诱导的整体膜蛋白。这种蛋白质是Vpu抵消的限制因子,以刺激病毒颗粒(病毒粒子)从受感染的宿主细胞释放。我们和其他人已经证明BST2直接将新生病毒粒子固定在感染细胞的质膜上;Vpu通过将BST2从质膜上的作用部位移除来抵消这一点;BST2在体内响应HIV复制时上调;BST2通过诱导NF-kB转录活性发挥信号和病毒感应功能。后一项发现符合一种新兴的范式,即逆转录病毒限制因子在先天免疫反应中具有多方面的作用。此外,该领域已经有证据表明,在SIVcpz从黑猩猩传播给人类时,HIV-1 Vpu特异性适应获得作为BST2拮抗剂的活性。现在需要回答几个关键问题,这些问题是该提案具体目标的基础:1)蛋白质限制和信号活动的分子决定因素和拓扑结构是什么?2)除了含有泛素连接酶复合物的TrCP外,支持BST2拮抗的细胞辅助因子有哪些? Vpu是如何与它们相互作用的?3) BST2如何激活NF-¿B并检测病毒基因表达?BST2是否促进了适应性免疫反应的某些方面?4) vpu介导的BST2拮抗是否有助于HIV-1的传播?通过本文提出的工作,我们希望了解BST2的系留和信号功能如何在结构上集成;Vpu如何调节BST2拮抗限制和信号传导;BST2信号和响应病毒基因表达和组装的机制;BST2是否促进适应性免疫;以及是否有任何与BST2相关的Vpu功能在个体间传播的HIV-1变异中得到优化。我们期望支持或拒绝bst2拮抗是HIV-1逃避免疫监视并在人类宿主中建立持续感染能力的一个重要方面的观点。
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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John C. Guatelli其他文献
John C. Guatelli的其他文献
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{{ truncateString('John C. Guatelli', 18)}}的其他基金
High-Throughput Screening for Multifunctional Nef Inhibitors: Targeting HIV through Revitalizing Immune Defense Mechanisms
多功能 Nef 抑制剂的高通量筛选:通过振兴免疫防御机制靶向 HIV
- 批准号:
10116282 - 财政年份:2020
- 资助金额:
$ 44.7万 - 项目类别:
High-Throughput Screening for Multifunctional Nef Inhibitors: Targeting HIV through Revitalizing Immune Defense Mechanisms
多功能 Nef 抑制剂的高通量筛选:通过振兴免疫防御机制靶向 HIV
- 批准号:
10010308 - 财政年份:2020
- 资助金额:
$ 44.7万 - 项目类别:
Activating Latently Infected Cells Using Specific Antigens Including Those of HIV-1
使用特定抗原(包括 HIV-1 抗原)激活潜伏感染细胞
- 批准号:
9206464 - 财政年份:2016
- 资助金额:
$ 44.7万 - 项目类别:
Involvement of the C-terminus of HIV-1 Vpu in Enhancement of Virion Release
HIV-1 Vpu C 末端参与增强病毒粒子释放
- 批准号:
8790372 - 财政年份:2014
- 资助金额:
$ 44.7万 - 项目类别:
Viral Hijacking of Host Membrane Trafficking Pathways
宿主膜运输途径的病毒劫持
- 批准号:
8601167 - 财政年份:2013
- 资助金额:
$ 44.7万 - 项目类别:
Viral Hijacking of Host Membrane Trafficking Pathways
宿主膜运输途径的病毒劫持
- 批准号:
8779706 - 财政年份:2013
- 资助金额:
$ 44.7万 - 项目类别:
Inhibiting Immune Evasion by HIV-1 Nef to Facilitate Eradication
抑制 HIV-1 Nef 的免疫逃避以促进根除
- 批准号:
8770025 - 财政年份:2013
- 资助金额:
$ 44.7万 - 项目类别:
Inhibiting Immune Evasion by HIV-1 Nef to Facilitate Eradication
抑制 HIV-1 Nef 的免疫逃避以促进根除
- 批准号:
8656289 - 财政年份:2013
- 资助金额:
$ 44.7万 - 项目类别:
Viral Hijacking of Host Membrane Trafficking Pathways
宿主膜运输途径的病毒劫持
- 批准号:
8542438 - 财政年份:2013
- 资助金额:
$ 44.7万 - 项目类别:
ULTRASTRUCTURAL LOCALIZATION OF THE HOST ANTIVIRAL PROTEIN BST-2
宿主抗病毒蛋白 BST-2 的超微结构定位
- 批准号:
8361924 - 财政年份:2011
- 资助金额:
$ 44.7万 - 项目类别:
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