Mutation of a single residue renders human tetherin resistant to HIV-1 Vpu-mediated depletion.
Mutation of a single residue renders human tetherin resistant to HIV-1 Vpu-mediated depletion.
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DOI：
10.1371/journal.ppat.1000443
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发表时间：
2009-05
期刊：
影响因子：
6.7
通讯作者：
Towers GJ
中科院分区：
文献类型：
--
作者：
Gupta RK;Hué S;Schaller T;Verschoor E;Pillay D;Towers GJ
最近鉴定的限制性因子tetherin/BST-2/CD 317是一种干扰素诱导的跨膜蛋白，其在不存在HIV-1对抗病毒蛋白U（Vpu）的情况下限制HIV-1颗粒释放。已知尽管存在Vpu，但在用1型干扰素刺激后，可以使坦塔罗斯猴CV1细胞不允许HIV-1释放，这表明系链蛋白对病毒对抗措施如Vpu具有物种特异性敏感性。在这里，我们表明，坦塔罗斯猴拴系蛋白限制HIV-1的近两个数量级，但与人类拴系蛋白的坦塔罗斯蛋白是不敏感的HIV-1 Vpu。我们已经调查了tetherin的敏感性Vpu使用积极的选择分析，寻找证据进化之间的冲突tetherin和病毒的对策。我们提供的证据表明，拴在灵长类动物进化过程中经历了积极的选择。人类系链蛋白跨膜帽中单个氨基酸（显示阳性选择的证据）突变为坦塔罗斯猴（T45 I）中的单个氨基酸，显著影响对HIV-1 Vpu的敏感性，但不影响抗病毒活性。最后，我们提供的证据表明，细胞稳态水平的拴系蛋白大大降低了Vpu，T45 I突变消除了这种影响。这项研究提供的证据表明，拴系蛋白是重要的，在保护哺乳动物免受病毒感染，和HIV-1 Vpu介导的对策是专门适应于对人类拴系蛋白。它还强调了选择分析的力量，以阐明宿主-病毒相互作用的分子细节。这项工作表明，拴系蛋白结合剂可能会保护它免受病毒编码的对抗措施，从而产生强大的抗病毒药物。在哺乳动物的进化过程中，致病性病毒一直在感染它们，施加选择性压力以进化出限制或消除这些寄生虫的系统。例如，称为限制因子的细胞内蛋白质通过靶向重要的病毒过程来特异性地限制病毒感染。限制因子tetherin将新形成的HIV-1病毒体拴在受感染细胞的表面，防止流出和进一步感染。为了抵消tetherin，HIV-1编码了一种称为Vpu的膜相关蛋白，它消除了tetherin的活性。在这里，我们表明，HIV-1 Vpu是无活性的Tetherin从坦塔罗斯猴，这是由于一个单一的氨基酸，不同的人类和坦塔罗斯猴Tetherin序列。在这个位置的正选择的证据表明，病毒感染提供了达尔文的选择压力，导致这种变化。我们还表明，Vpu的表达导致细胞中的tetherin蛋白的损失。人类系链蛋白的突变保护其免受HIV-1 Vpu活性的影响，允许功能性蛋白表达和限制病毒释放。这项研究强调了选择分析揭示抗病毒特异性决定因素的实用性，并为红皇后假说所描述的宿主病毒军备竞赛提供了有力证据。
The recently identified restriction factor tetherin/BST-2/CD317 is an interferon-inducible trans-membrane protein that restricts HIV-1 particle release in the absence of the HIV-1 countermeasure viral protein U (Vpu). It is known that Tantalus monkey CV1 cells can be rendered non-permissive to HIV-1 release upon stimulation with type 1 interferon, despite the presence of Vpu, suggesting species-specific sensitivity of tetherin proteins to viral countermeasures such as Vpu. Here we demonstrate that Tantalus monkey tetherin restricts HIV-1 by nearly two orders of magnitude, but in contrast to human tetherin the Tantalus protein is insensitive to HIV-1 Vpu. We have investigated tetherin's sensitivity to Vpu using positive selection analyses, seeking evidence for evolutionary conflict between tetherin and viral countermeasures. We provide evidence that tetherin has undergone positive selection during primate evolution. Mutation of a single amino acid (showing evidence of positive selection) in the trans-membrane cap of human tetherin to that in Tantalus monkey (T45I) substantially impacts on sensitivity to HIV-1 Vpu, but not on antiviral activity. Finally, we provide evidence that cellular steady state levels of tetherin are substantially reduced by Vpu, and that the T45I mutation abrogates this effect. This study provides evidence that tetherin is important in protecting mammals against viral infection, and that the HIV-1 Vpu–mediated countermeasure is specifically adapted to act against human tetherin. It also emphasizes the power of selection analyses to illuminate the molecular details of host–virus interactions. This work suggests that tetherin binding agents might protect it from viral encoded countermeasures and thus make powerful antivirals. Pathogenic viruses have been infecting mammals throughout their evolution, exerting selective pressure to evolve systems to limit or eliminate these parasites. For example, intracellular proteins called restriction factors specifically restrict viral infection by targeting important viral processes. The restriction factor tetherin tethers newly formed HIV-1 virions to the surface of infected cells, preventing egress and further infection. In order to counteract tetherin, HIV-1 encodes a membrane-associated protein called Vpu that abrogates tetherin activity. Here we show that HIV-1 Vpu is inactive against tetherin from Tantalus monkeys and that this is due to a single amino acid that differs between human and tantalus monkey tetherin sequences. Evidence for positive selection at this position suggests that viral infections have provided the Darwinian selective pressure leading to this change. We also show that Vpu expression leads to a loss of tetherin protein in cells. Mutation of human tetherin protects it from HIV-1 Vpu activity, allowing functional protein expression and restriction of viral release. This study underlines the utility of selection analyses to reveal determinants of antiviral specificity and is strong evidence for the host–virus arms race described by the Red Queen hypothesis.
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发表时间：
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