Vpu of a Simian Immunodeficiency Virus Isolated from Greater Spot-Nosed Monkey Antagonizes Human BST-2 via Two AxxxxxxxW Motifs.
Vpu of a Simian Immunodeficiency Virus Isolated from Greater Spot-Nosed Monkey Antagonizes Human BST-2 via Two AxxxxxxxW Motifs.
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从大斑鼻猴中分离出的猿猴免疫缺陷病毒的 Vpu 通过两个 AxxxxxxxW 基序拮抗人类 BST-2。
DOI：
10.1128/jvi.01669-19
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发表时间：
2020
影响因子：
5.4
通讯作者：
Yamaoka,Shoji
中科院分区：
文献类型：
--
作者：
Yao,Weitong;Yoshida,Takeshi;Hashimoto,Saki;Takeuchi,Hiroaki;Strebel,Klaus;Yamaoka,Shoji
BST-2/CD 317/tetherin是一种宿主跨膜蛋白，通过将新生病毒体束缚在质膜上而有效抑制人类免疫缺陷病毒1型（HIV-1）病毒体释放。病毒蛋白U（Vpu）是由HIV-1以及一些感染野生黑猩猩、大猩猩或猴子的猿免疫缺陷病毒（SIV）（分别为SIVcpz、SIVgor或SIVgsn/SIVmon/SIVmus）编码的辅助蛋白。HIV-1 Vpu直接结合并下调人BST-2。由于BST-2的氨基酸序列在不同动物种属之间存在差异，因此拮抗作用具有高度的种属特异性。在这里，我们表明，Vpu蛋白从几个SIVcpz，SIVgsn，SIVmon，或SIVMus分离物不能拮抗人类BST-2。只有来自SIVgsn分离物（SIVgsn-99 CM 71 [SIVgsn 71]）的Vpu能够拮抗人BST-2以及其天然宿主大斑鼻猴（GSN）的BST-2。该SIVgsn Vpu与人BST-2相互作用，下调细胞表面人BST-2表达，并在人BST-2存在下促进HIV-1病毒体释放。HIV-1 NL 4 -3Vpu跨膜结构域中的14 AxxxxxxxW 22基序对拮抗人BST-2具有重要作用，而SIVgsn 71 Vpu中存在两个AxxxxxxxW基序（A22 W30和A25 W33）。SIVgsn 71 Vpu仅需要A22 W30基序就能拮抗GSN BST-2，表明这种拮抗作用的机制类似于HIV-1 NL 4 -3Vpu对抗人BST-2的机制。有趣的是，SIVgsn 71 Vpu需要两个AxxxxxxxW（A22 W30和A25 W33）基序来拮抗人BST-2，这表明SIVgsn 71 Vpu对抗人BST-2的方式尚未确定。这些结果意味着进化的影响灵长类动物BST-2慢病毒Vpu. IMPORTANCEGeneticalterations赋予选择性优势，在保护生命威胁病原体的进化过程中保持。事实上，BST-2的氨基酸序列在灵长类动物中不同，它们对病毒蛋白的易感性具有物种特异性，这表明这种遗传多样性是通过宿主和病原体之间的进化控制平衡而产生的。HIV-1的M（主要）基团被认为是来自SIVcpz，它利用Nef而不是Vpu来对抗黑猩猩BST-2。然而，SIVcpz Nef不能拮抗人BST-2，因此在HIV-1的情况下再次选择Vpu作为抗人BST-2的拮抗剂。对Vpu如何失去和获得这种能力的研究，以及SIVgsn 71 Vpu与人或GSN BST-2结合并下调的不同机制，可能有助于解释这种慢病毒蛋白作为宿主-病原体相互作用的结果的进化。
BST-2/CD317/tetherin is a host transmembrane protein that potently inhibits human immunodeficiency virus type 1 (HIV-1) virion release by tethering the nascent virions to the plasma membrane. Viral protein U (Vpu) is an accessory protein encoded by HIV-1 as well as by some simian immunodeficiency viruses (SIVs) infecting wild chimpanzees, gorillas, or monkeys (SIVcpz, SIVgor, or SIVgsn/SIVmon/SIVmus, respectively). HIV-1 Vpu directly binds to and downregulates human BST-2. The antagonism is highly species specific because the amino acid sequences of BST-2 are different among animal species. Here, we show that Vpu proteins from several SIVcpz, SIVgsn, SIVmon, or SIVmus isolates fail to antagonize human BST-2. Only Vpu from an SIVgsn isolate (SIVgsn-99CM71 [SIVgsn71]) was able to antagonize human BST-2 as well as BST-2 of its natural host, greater spot-nosed monkey (GSN). This SIVgsn Vpu interacted with human BST-2, downregulated cell surface human BST-2 expression, and facilitated HIV-1 virion release in the presence of human BST-2. While the unique14AxxxxxxxW22motif in the transmembrane domain of HIV-1NL4-3Vpu was reported to be important for antagonizing human BST-2, we show here that two AxxxxxxxW motifs (A22W30and A25W33) exist in SIVgsn71 Vpu. Only the A22W30motif was needed for SIVgsn71 Vpu to antagonize GSN BST-2, suggesting that the mechanism of this antagonism resembles that of HIV-1NL4-3Vpu against human BST-2. Interestingly, SIVgsn71 Vpu requires two AxxxxxxxW (A22W30and A25W33) motifs to antagonize human BST-2, suggesting an as-yet-undefined way that SIVgsn71 Vpu works against human BST-2. These results imply an evolutionary impact of primate BST-2 on lentiviral Vpu.IMPORTANCEGenetic alterations conferring a selective advantage in protecting from life-threating pathogens are maintained during evolution. In fact, the amino acid sequences of BST-2 differ among primate animals and their susceptibility to viral proteins is species specific, suggesting that such genetic diversity has arisen through the evolutionarily controlled balance between the host and pathogens. The M (main) group of HIV-1 is thought to be derived from SIVcpz, which utilizes Nef, but not Vpu, to antagonize chimpanzee BST-2. SIVcpz Nef is, however, unable to antagonize human BST-2, and Vpu was consequently chosen again as an antagonist against human BST-2 in the context of HIV-1. Studies on how Vpu lost and acquired this ability, together with the distinct mechanisms by which SIVgsn71 Vpu binds to and downregulates human or GSN BST-2, may help to explain the evolution of this lentiviral protein as a result of host-pathogen interactions.