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，许多包裹病毒通过从质膜中萌发而释放出感染细胞。最近，干扰素诱导的膜蛋白Tetherin/ BST2被确定为有效的宿主抗病毒因子，抑制了一系列包膜病毒（例如HIV-1）的释放。 Tetherin直接将病毒转移到宿主质膜上，并与细胞内吞机制相互作用，以进行病毒内在化和降解。 HIV-1病毒蛋白U（VPU）通过募集宿主的细胞E3泛素连接酶来拮抗Tetherin，从而将其引导到宿主途径，以识别泛素作为运输信号，例如蛋白质/溶酶体/溶酶体脱落和/或/或内植物学。我们研究的总体目标是建立Tetherin限制包膜病毒释放的机制以及病毒与Tetherin拮抗的机制。我们将通过使用多学科的方法结合最先进的生化和生物物理技术，功能病毒学，冷冻电子显微镜和电子层析成像以及X射线晶体学方法来确定Tetherin功能的生化和结构原理，从而研究病毒 - 细胞相互作用hiv-1 Attetherin和tentery ninin ninin，从而确定他们的生化和结构原理。我们的工作将允许阐明主要的宿主免疫防御机制，并显着促进我们对各种宿主 - 病毒互动的理解。从我们的研究中得出的信息将为开发艾滋病毒和其他病毒的新治疗干预措施而产生一个框架。此外，为我们的研究项目设计的实验系统将为宿主病原关系的研究提供宝贵的新工具。