Simian immunodeficiency virus envelope glycoprotein counteracts tetherin/BST-2/CD317 by intracellular sequestration
Simian immunodeficiency virus envelope glycoprotein counteracts tetherin/BST-2/CD317 by intracellular sequestration
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DOI：
10.1073/pnas.0907075106
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发表时间：
2009-12-08
影响因子：
11.1
通讯作者：
Towers, Greg J.
中科院分区：
文献类型：
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作者：
Gupta, Ravindra K.;Mlcochova, Petra;Towers, Greg J.
Tetherin是一种IFN诱导的限制性因子，在没有HIV-1对策病毒蛋白U（Vpu）的情况下抑制HIV-1颗粒释放。尽管在来自黑猩猩、大斑鼻猴、胡子猴和莫纳猴的HIV-1和猿猴免疫缺陷病毒中普遍存在，但其他灵长类慢病毒不编码Vpu蛋白。在这里，我们证明，SIV从坦塔罗斯猴（SIVtan）编码的包膜糖蛋白（SIVtan Env）能够抵消拴从坦塔罗斯猴，恒河猴，白眉猴，和人类，但不是从猪。我们表明，敏感性Vpu，但不是SIVtan Env可以转移与人类栓蛋白跨膜区。我们还确定了一个突变的拴系蛋白的胞外结构域，几乎完全废除了敏感性的人拴系蛋白SIVtan Env不损害抗病毒活性或敏感性的Vpu。SIVtan Env表达导致表面栓系蛋白的减少，以及栓系蛋白与成熟表面相关病毒共定位的减少。免疫电子显微镜揭示了SIVtan Env与系链蛋白在细胞内管泡结构中的共定位，表明系链蛋白被隔离远离细胞表面的出芽病毒体。沿着HIV-1 Vpu和SIV Nef，包膜糖蛋白是第三个也是最广泛的慢病毒编码的栓系蛋白对抗措施。我们的观察强调了Tetherin在保护哺乳动物免受病毒感染方面的重要性，并表明HIV-1 Vpu抑制剂可以选择活性包膜突变体。
Tetherin is an IFN-inducible restriction factor that inhibits HIV-1 particle release in the absence of the HIV-1 countermeasure, viral protein U (Vpu). Although ubiquitous in HIV-1 and simian immunodeficiency viruses from chimpanzees, greater spot nosed monkeys, mustached monkeys, and Mona monkeys, other primate lentiviruses do not encode a Vpu protein. Here we demonstrate that SIV from Tantalus monkeys (SIVtan) encodes an envelope glycoprotein (SIVtan Env) able to counteract tetherin from Tantalus monkeys, rhesus monkeys, sooty mangabeys, and humans, but not from pigs. We show that sensitivity to Vpu but not SIVtan Env can be transferred with the human tetherin transmembrane region. We also identify a mutation in the tetherin extracellular domain, which almost completely abolishes sensitivity of human tetherin to SIVtan Env without compromising antiviral activity or sensitivity to Vpu. SIVtan Env expression results in a reduction of surface tetherin, as well as reduction in tetherin co-localization with mature surface-associated virus. Immuno-electron microscopy reveals co-localization of SIVtan Env with tetherin in intracellular tubulo-vesicular structures, suggesting that tetherin is sequestered away from budding virions at the cell surface. Along with HIV-1 Vpu and SIV Nef, envelope glycoprotein is the third and most broadly active lentiviral-encoded tetherin countermeasure to be described. Our observations emphasize the importance of tetherin in protecting mammals against viral infection and suggest that HIV-1 Vpu inhibitors may select active envelope mutants.