HIV-1 Vpu and BST-2/CD317

描述（由申请人提供）：HIV-1 Vpu通过克服在感染细胞内和细胞表面保留新生病毒粒子的细胞抑制剂来增强病毒粒子从感染细胞中的释放。这种抑制剂的身份最近被揭示：它是跨膜，gpi锚定蛋白BST-2，也称为HM1.24， CD317或“tetherin”。BST-2似乎能够影响多种包膜病毒粒子，这表明在宿主防御包括HIV-1在内的病毒方面具有广泛的作用。这里提出的研究有三个具体目的：1)揭示BST-2如何在感染细胞上保留HIV-1病毒粒子；2)确定Vpu如何对抗这种限制；3)了解BST-2在先天免疫应答中的调控作用，探讨BST-2在抗原提呈细胞中的潜在功能。这些目标将通过协调一致的实验方法来实现，包括BST-2和Vpu的靶向诱变，BST-2和Vpu之间相互作用的表征，Vpu对BST-2细胞内运输和病毒粒子结合的影响的分析，以及BST-2在初级T淋巴细胞和抗原提呈细胞中的调节和功能的分析。当这些目标完成后，我们将知道BST-2如何在感染细胞上保留病毒粒子，Vpu如何抵消这种蛋白质，BST-2在先天免疫反应中如何被调节，以及它是否在适应性免疫反应中抗原提呈细胞摄取病毒粒子中发挥作用。公共卫生相关性：BST-2是一种新发现的宿主细胞蛋白，可保留感染细胞上的病毒颗粒，包括HIV-1病毒颗粒。HIV-1蛋白Vpu抵消了这种宿主防御。本研究旨在探讨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.