Tokarev Andrey, Skasko Mark, Fitzpatrick Kathleen, Guatelli John
Department of Medicine, University of California San Diego, California 92093-0679, USA.
AIDS Res Hum Retroviruses. 2009 Dec;25(12):1197-210. doi: 10.1089/aid.2009.0253.
Pathogenic microorganisms encode proteins that antagonize specific aspects of innate or adaptive immunity. Just as the study of the HIV-1 accessory protein Vif led to the identification of cellular cytidine deaminases as host defense proteins, the study of HIV-1 Vpu recently led to the discovery of the interferon-induced transmembrane protein BST-2 (CD317; tetherin) as a novel component of the innate defense against enveloped viruses. BST-2 is an unusually structured protein that restricts the release of fully formed progeny virions from infected cells, presumably by a direct retention mechanism that is independent of any viral protein target. Its spectrum of activity includes at least four virus families: retroviruses, filoviruses, arenaviruses, and herpesviruses. Viral antagonists of BST-2 include HIV-1 Vpu, HIV-2 and SIV Env, SIV Nef, the Ebola envelope glycoprotein, and the K5 protein of KSHV. The mechanisms of antagonism are diverse and currently include viral cooption of cellular endosomal trafficking and protein degradation pathways, including those mediated by ubiquitination. Orthologs of human BST-2 are present in mammals. Primate BST-2 proteins are differentially sensitive to antagonism by lentiviral Vpu and Nef proteins, suggesting that BST-2 has subjected lentiviruses to evolutionary pressure and presents barriers to cross-species transmission. BST-2 functions not only as an effector of the interferon-induced antiviral response but also as a negative feedback regulator of interferon production by plasmacytoid dendritic cells. Future work will focus on the role and regulation of BST-2 during the innate response to viral infection, on the mechanisms of restriction and of antagonism by viral gene products, and on the role of BST-2 in primate lentiviral evolution. The augmentation of BST-2 activity and the inhibition of virally encoded antagonists, in particular Vpu, represent new approaches to the prevention and treatment of HIV-1 infection.
致病微生物编码的蛋白质可对抗先天性或适应性免疫的特定方面。正如对HIV-1辅助蛋白Vif的研究导致细胞胞苷脱氨酶被鉴定为宿主防御蛋白一样，最近对HIV-1 Vpu的研究导致发现干扰素诱导的跨膜蛋白BST-2（CD317；束缚素）是针对包膜病毒的先天性防御的新组分。BST-2是一种结构异常的蛋白质，它可能通过独立于任何病毒蛋白靶点的直接保留机制，限制感染细胞中完全形成的子代病毒颗粒的释放。其活性谱至少包括四个病毒家族：逆转录病毒、丝状病毒、沙粒病毒和疱疹病毒。BST-2的病毒拮抗剂包括HIV-1 Vpu、HIV-2和SIV Env、SIV Nef、埃博拉病毒包膜糖蛋白以及KSHV的K5蛋白。拮抗机制多种多样，目前包括病毒对细胞内体运输和蛋白质降解途径的利用，包括那些由泛素化介导的途径。人类BST-2的直系同源物存在于哺乳动物中。灵长类动物的BST-2蛋白对慢病毒Vpu和Nef蛋白的拮抗作用具有不同的敏感性，这表明BST-2对慢病毒施加了进化压力，并对跨物种传播构成了障碍。BST-2不仅作为干扰素诱导的抗病毒反应的效应物发挥作用，还作为浆细胞样树突状细胞产生干扰素的负反馈调节因子。未来的工作将集中在BST-2在病毒感染先天性反应中的作用和调节、病毒基因产物的限制和拮抗机制以及BST-2在灵长类慢病毒进化中的作用。增强BST-2活性和抑制病毒编码的拮抗剂，特别是Vpu，代表了预防和治疗HIV-1感染的新方法。
