Mechanisms of enveloped virus tethering by tetherin and viral countermeasures

系链蛋白束缚包膜病毒的机制和病毒对策

• 批准号: 8467997
• 负责人: Yong Xiong
• 金额: $ 38.48万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8467997
• 关键词: Antiviral Agents; Biochemical; C-terminal; Calorimetry; Cell membrane; Cells; Complex; Cryoelectron Microscopy; Cullin 1; Cytoplasmic Tail; Data; Defense Mechanisms; Development; Electron Microscopy; Goals; HIV; HIV Infections; HIV-1; Host Defense; Immune; Infection; Interferons; Lead; Maps; Membrane Proteins; Methods; Modeling; Mutagenesis; Pathway interactions; Polyubiquitination; Property; Recruitment Activity; Research; Research Project Grants; Roentgen Rays; Signal Transduction; Structure; System; Systems Development; Techniques; Testing; Titrations; Ubiquitin; Viral; Viral Proteins; Virus; Work; analytical ultracentrifugation; base; electron tomography; insight; interdisciplinary approach; interest; novel therapeutic intervention; pathogen; public health relevance; segregation; tool; trafficking; ubiquitin-protein ligase; virology

DESCRIPTION (provided by applicant): To spread infection, many enveloped viruses are released from infected cells by budding off of the plasma membrane. Recently, an interferon-induced membrane protein, tetherin/ BST2, has been identified as a potent host antiviral factor inhibiting the release of a range of enveloped viruses, such as HIV-1. Tetherin directly tethers viruses to the host plasma membrane and interacts with the cellular endocytic machinery for viral internalization and degradation. HIV-1 viral protein U (Vpu) antagonizes tetherin by recruiting a host cellular E3 ubiquitin ligase to polyubiquitinate tetherin, thereby directing it to host pathways recognizing ubiquitin as a trafficking signal such as proteosomal/lysosomal degradation and/or endosomal segregation. The overall goal of our study is to establish the mechanisms by which tetherin restricts the release of enveloped viruses and the mechanisms by which viruses antagonize tetherin. We will achieve our goal by using a multidisciplinary approach combining cutting-edge biochemical and biophysical techniques, functional virology, cryo-electron microscopy and electron tomography, and X-ray crystallographic methods to determine the biochemical and structural principles of tetherin function, to investigate viral-cellular interactions in HIV-1 antagonization of tetherin, and to test their functional significance. Our work will allow for the elucidation of a major host immune defense mechanism and significantly advance our understanding of a diverse range of host-viral interplays. Information derived from our studies will generate a framework for the development of new therapeutic interventions of HIV and other viruses. Moreover, the experimental systems devised for our research project will provide valuable new tools for the studies of host-pathogen relationships.

描述（由申请人提供）：为了传播感染，许多包膜病毒通过质膜出芽从受感染的细胞中释放出来。最近，一种干扰素诱导的膜蛋白，tetherin/BST2，已被确定为一种有效的宿主抗病毒因子，可抑制一系列包膜病毒（例如 HIV-1）的释放。 Tetherin 直接将病毒束缚在宿主质膜上，并与细胞内吞机制相互作用，实现病毒内化和降解。 HIV-1 病毒蛋白 U (Vpu) 通过招募宿主细胞 E3 泛素连接酶对系链蛋白进行多聚泛素化来拮抗系链蛋白，从而引导其进入将泛素识别为运输信号的宿主途径，例如蛋白体/溶酶体降解和/或内体分离。我们研究的总体目标是建立系链蛋白限制包膜病毒释放的机制以及病毒拮抗系链蛋白的机制。我们将通过采用多学科方法，结合尖端生化和生物物理技术、功能病毒学、冷冻电子显微镜和电子断层扫描以及 X 射线晶体学方法来确定系链蛋白功能的生化和结构原理，以研究病毒，从而实现我们的目标。 -HIV-1拮抗tetherin中的细胞相互作用，并测试其功能意义。我们的工作将有助于阐明主要的宿主免疫防御机制，并显着增进我们对多种宿主与病毒相互作用的理解。从我们的研究中获得的信息将为开发艾滋病毒和其他病毒的新治疗干预措施提供一个框架。此外，为我们的研究项目设计的实验系统将为宿主与病原体关系的研究提供有价值的新工具。