HIV-1 Vpu and BST-2/CD317

描述(申请人提供)：HIV-1编码调节宿主细胞环境的蛋白质，以优化病毒复制并避免宿主防御。辅助蛋白VPU部分通过拮抗宿主蛋白BST2(也称为HM1.24、CD317和Tetherin)的活性来实现这一点。BST2是一种干扰素诱导的整膜蛋白。这种蛋白质是VPU中和刺激病毒颗粒(病毒粒子)从受感染的宿主细胞释放的限制因子。我们和其他人已经证明，BST2直接将新生病毒粒子固定在受感染细胞的质膜上；VPU通过将BST2从其在质膜上的作用部位移除来抵消这种作用；BST2在体内响应艾滋病毒复制而上调；以及BST2通过诱导核因子-kB转录活性发挥信号和病毒传感功能。后者的发现符合一个新兴的范式，在这个范式中，逆转录病毒限制因子在先天性免疫反应中具有多方面的作用。此外，该领域还发现证据表明，HIV-1 VPU在将SIVcpz从黑猩猩传播给人类时，专门适应获得BST2拮抗剂的活性。目前需要回答的几个关键问题是：1)蛋白质限制和信号活性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体的TrCP外，还有哪些细胞辅助因子支持BST2的拮抗作用，VPU是如何与它们相互作用的？3)BST2如何激活NF-βB并检测病毒基因的表达？BST2是否促进获得性免疫反应的各个方面？4)VPU介导的BST2拮抗作用是否有助于HIV-1的传播？通过这里提出的工作，我们希望了解BST2的拴系和信号功能是如何在结构上整合的；VPU如何调节BST2以对抗限制和信号；BST2信号和响应病毒基因表达和组装的机制；BST2是否促进获得性免疫；以及是否有任何与BST2相关的VPU功能在HIV-1个体之间传播的变种中得到优化。我们希望支持或反对BST2拮抗是HIV-1 S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的观点。

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.