Mechanisms of enveloped virus tethering by tetherin and viral countermeasures

描述（由申请人提供）：为了传播感染，许多包膜病毒通过从质膜出芽而从被感染的细胞中释放出来。最近，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（如HIV-1）的释放。系链蛋白直接将病毒拴在宿主质膜上，并与细胞内吞机制相互作用，使病毒内化和降解。HIV-1病毒蛋白U （Vpu）通过募集宿主细胞E3泛素连接酶使tetherin泛素化，从而将其引导到识别泛素作为运输信号的宿主途径，如蛋白体/溶酶体降解和/或内体分离，从而对抗tetherin。本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拮抗tetherin的机制。我们将采用多学科方法，结合尖端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断层扫描以及x射线晶体学方法来确定tetherin功能的生化和结构原理，研究tetherin在HIV-1拮抗中的病毒-细胞相互作用，并测试其功能意义。我们的工作将允许阐明一个主要的宿主免疫防御机制，并显着推进我们对宿主-病毒相互作用的多种理解。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研究宿主-病原体关系提供有价值的新工具。

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.