HIV-1 Vpu and BST-2/CD317

描述（由申请方提供）：HIV-1 Vpu通过克服将新生病毒体保留在感染细胞内和感染细胞上的细胞抑制剂，增强病毒体从感染细胞中的释放。这种抑制剂的身份最近已经被揭示：它是跨膜的GPI锚定蛋白BST-2，也称为HM 1.24，CD 317或“tetherin”。“BST-2似乎能够影响多种包膜病毒体，这表明它在宿主防御包括HIV-1在内的病毒方面发挥着广泛的作用。本研究有三个具体目的：1）揭示BST-2如何将HIV-1病毒粒子保留在感染细胞上; 2）确定Vpu如何拮抗这种限制; 3）了解BST-2在先天免疫应答中的调节，并探索BST-2在抗原呈递细胞中的潜在功能。这些目标将使用一个协调一致的实验方法，包括BST-2和Vpu的靶向诱变，BST-2和Vpu之间的相互作用的表征，分析Vpu对BST-2的细胞内运输和病毒体掺入的影响，以及BST-2在原代T淋巴细胞和抗原呈递细胞中的调节和功能的分析。当这些目标完成时，我们将知道BST-2如何在感染细胞上保留病毒体，Vpu如何抵消这种蛋白质，BST-2在先天免疫应答期间如何调节，以及它是否在适应性免疫应答期间通过抗原呈递细胞摄取病毒体中发挥作用。BST-2是一种新发现的宿主细胞蛋白，它可以保留病毒颗粒，包括感染细胞上的HIV-1。HIV-1蛋白Vpu抵消了这种宿主防御。这项研究旨在探索BST-2如何保留病毒颗粒，Vpu如何拮抗这种活性，以及BST-2如何在免疫系统的原代细胞中受到调节。

DESCRIPTION (provided by applicant): HIV-1 Vpu enhances the release of virions from infected cells by overcoming a cellular inhibitor that retains nascent virions within and on infected cells. The identity of this inhibitor has recently been revealed: it is the transmembrane, GPI-anchored protein BST-2, also known as HM1.24, CD317, or "tetherin." BST-2 seems able to affect diverse enveloped virions, suggesting a broad role in the host defense against viruses including HIV-1. The research proposed here has three specific aims: 1) to reveal how BST-2 retains HIV-1 virions on infected cells; 2) to determine how Vpu antagonizes this restriction; 3) to understand the regulation of BST-2 during the innate immune response and to explore the potential function of BST-2 in antigen presenting cells. These aims will be pursued using a concerted experimental approach including targeted mutagenesis of BST-2 and Vpu, characterization of the interaction between BST-2 and Vpu, analysis of the effects of Vpu on the intracellular trafficking and virion-incorporation of BST-2, and analysis of the regulation and function of BST-2 in primary T lymphocytes and antigen presenting cells. When these aims are completed, we will know how BST-2 retains virions on infected cells, how Vpu counteracts this protein, how BST-2 is regulated during the innate immune response, and whether it plays a role in the uptake of virions by antigen presenting cells during the adaptive immune response. PUBLIC HEALTH RELEVANCE: BST-2 is a newly identified host-cell protein that retains virus particles including those of HIV-1 on infected cells. The HIV-1 protein Vpu counteracts this host defense. This research is designed to explore how BST-2 retains virus particles, how Vpu antagonizes this activity, and how BST-2 is regulated within primary cells of the immune system.