HIV-1 Vpu and BST-2/CD317

HIV-1编码的蛋白质调节宿主细胞环境，以优化病毒复制并避免宿主 防御。辅助蛋白VPU部分地通过拮抗宿主蛋白的活性来实现这一点 BST2(也称为HM1.24、CD317和Tetherin)。BST2是一种干扰素诱导的整体膜 蛋白。这种蛋白质是VPU中和刺激病毒颗粒释放的限制因子。 (病毒粒子)从受感染的宿主细胞。我们和其他人已经证明了BST2直接持有新生病毒粒子到 受感染细胞的质膜；VPU通过将BST2从其作用部位 质膜；BST2在体内响应艾滋病毒复制而上调；以及BST2服务于 信号和病毒感知功能通过诱导核因子-κB的转录活性来实现。后者的发现符合 逆转录病毒限制因子在先天免疫过程中发挥多方面作用的新范式 回应。此外，该领域已找到证据表明，艾滋病毒-1 VPU特别适应于获得活动。 作为BST2的拮抗剂，在SIVcpz从黑猩猩传播到人类时。 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)蛋白质的限制和信号活性的分子决定因素和拓扑结构是什么？2)在 除了含有泛素连接酶复合体的β-TrCP外，还有哪些细胞辅助因子支持 Bst2的拮抗作用及其与VPU的相互作用？3)Bst2如何激活NF-κB并检测病毒 基因表达？BST2是否促进获得性免疫反应的各个方面？4)VPU介导的 BST2的拮抗作用有助于HIV-1的传播？ 通过这里提出的工作，我们希望了解BST2的系留和信令功能是如何 结构整合；VPU如何调节BST2以对抗限制和信号转导；通过 哪些BST2信号和响应病毒基因的表达和组装；BST2是否促进适应性 免疫力；以及是否有任何与BST2相关的VPU功能在HIV-1变种中进行了优化 在个体之间传播。我们希望支持或拒绝BST2-拮抗是一种 S逃脱免疫监视并在中国建立持续感染的能力的重要方面 人类的主人。

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-κB 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 β-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-κB 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.