HIV-1 Vpu and BST-2/CD317

描述（由申请人提供）：HIV-1编码调节宿主细胞环境以优化病毒复制并避免宿主防御的蛋白质。辅助蛋白Vpu部分通过拮抗宿主蛋白BST 2（也称为HM 1.24、CD 317和系链蛋白）的活性来实现这一点。BST 2是一种干扰素诱导的整合膜蛋白。这种蛋白质是Vpu对抗的限制因子，以刺激病毒颗粒（病毒体）从感染的宿主细胞中释放。我们和其他人已经表明，BST 2直接将新生病毒体保持在感染细胞的质膜上; Vpu通过将BST 2从其在质膜上的作用位点移除来抵消这一点; BST 2在体内响应HIV复制而上调;并且BST 2通过诱导NF-κ B转录活性来提供信号传导和病毒传感功能。后一个发现符合一个新兴的范式，其中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，该领域已经开发出证据表明，HIV-1 Vpu在将SIVcpz从黑猩猩传播给人类时特别适合作为BST 2的拮抗剂获得活性。现在需要回答几个关键问题，这些是该提案的具体目标的基础：1）蛋白质的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BST 2拮抗作用的细胞辅因子是什么？Vpu如何与它们相互作用？3)BST 2如何激活NF-B并检测病毒基因表达？BST 2是否促进了适应性免疫反应的各个方面？Vpu介导的BST 2拮抗作用是否有助于HIV-1的传播？通过本文的工作，我们希望了解BST 2的束缚和信号功能是如何在结构上整合的; Vpu如何调节BST 2以拮抗限制和信号; BST 2信号和响应病毒基因表达和组装的机制; BST 2是否促进适应性免疫;以及在个体之间传播的HIV-1变体中是否优化了与BST 2相关的任何Vpu功能。我们希望支持或拒绝这样的概念，即BST 2拮抗作用是HIV-1逃避免疫监视并在人类宿主中建立持续感染的能力的一个重要方面。

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.