HIV-1 Vpu and BST-2/CD317

描述(由申请人提供)：HIV-1 VPU通过克服一种将新生的病毒粒子保留在感染细胞内和感染细胞上的细胞抑制物来增强受感染细胞中病毒粒子的释放。这种抑制物的身份最近被揭示：它是跨膜的，GPI锚定蛋白BST-2，也被称为HM1.24，CD317，或“tetherin”。BST-2似乎能够影响不同的包膜病毒粒子，这表明在宿主对包括HIV-1在内的病毒的防御中具有广泛的作用。这项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如何拮抗这一限制；3)了解BST-2在先天免疫反应中的调节，并探索BST-2在抗原提呈细胞中的潜在功能。这些目标将通过一种协调一致的实验方法来实现，包括靶向突变BST-2和VPU，表征BST-2和VPU之间的相互作用，分析VPU对BST-2细胞内运输和病毒粒子掺入的影响，以及分析BST-2在原代T淋巴细胞和抗原提呈细胞中的调节和功能。当这些目标完成后，我们将知道BST-2是如何在感染细胞上保留病毒粒子的，VPU如何抵消这种蛋白质，BST-2在先天性免疫反应中是如何调节的，以及它是否在获得性免疫反应中抗原提呈细胞摄取病毒粒子中发挥作用。与公共卫生相关：BST-2是一种新发现的宿主细胞蛋白，它将包括HIV-1在内的病毒颗粒保留在感染细胞上。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如何拮抗这一活性，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.