Species-specific activity of HIV-1 Vpu and positive selection of tetherin transmembrane domain variants.
Species-specific activity of HIV-1 Vpu and positive selection of tetherin transmembrane domain variants.
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DOI：
10.1371/journal.ppat.1000300
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发表时间：
2009-02
期刊：
影响因子：
6.7
通讯作者：
Bieniasz, Paul D.
中科院分区：
文献类型：
--
作者：
McNatt, Matthew W.;Zang, Trinity;Hatziioannou, Theodora;Bartlett, Mackenzie;Ben Fofana, Ismael;Johnson, Welkin E.;Neil, Stuart J. D.;Bieniasz, Paul D.
Tetherin/BST-2/CD 317是最近鉴定的抗病毒蛋白，其阻断新生逆转录病毒和其他病毒颗粒从感染细胞的释放。一种HIV-1辅助蛋白Vpu是栓蛋白的拮抗剂。在这里，我们表明，积极的选择是显而易见的灵长类动物的tetherin序列和HIV-1 Vpu似乎有专门适应拮抗在人类和黑猩猩中发现的tetherin的变体。在恒河猴（rh）、非洲绿色猴（agm）和小鼠中发现的Tetherin变体能够抑制HIV-1颗粒释放，但对HIV-1 Vpu的拮抗作用具有抵抗力。值得注意的是，人和猴系链蛋白之间跨膜结构域的相互交换赋予了对Vpu的敏感性和抗性，将该蛋白质结构域鉴定为Vpu功能的关键决定因素。事实上，在跨膜结构域中的几个位置处的胡-拴蛋白和rh-tetherin之间的差异影响对Vpu拮抗作用的敏感性。两个改变，在胡-tetherin跨膜结构域，这对应于在rh-和agm-tetherin蛋白质中发现的差异，足以使胡-tetherin完全耐HIV-1 Vpu。有趣的是，跨膜和细胞质结构域序列在灵长类动物系栓蛋白表现出变化，在许多密码子，这可能是积极的选择的结果，这些变化中的一些与HIV-1 Vpu敏感性的决定因素相一致。总的来说，这些数据表明，作为由古老的病毒拮抗剂驱动的正选择的结果，拴系蛋白可以对病毒性人畜共患病施加屏障，并且HIV-1 Vpu蛋白专门靶向人/黑猩猩拴系蛋白中发现的跨膜结构域。Tetherin是一种细胞表面蛋白质，可作为抗病毒防御。它的功能是将新组装的HIV-1颗粒拴在感染细胞的表面，这样病毒颗粒就无法离开并传播到其他未感染的细胞。HIV-1具有一种名为Vpu的系链蛋白拮抗剂，可消除系链蛋白功能。我们发现，HIV-1是人类和黑猩猩的tetherin变体的有效拮抗剂，但不能拮抗两种猴子的tetherin。此外，我们发现，嵌入细胞膜的蛋白质部分的序列差异决定了它是否可以被Vpu拮抗。由于Vpu蛋白也是一种膜包埋蛋白，因此该结果表明Vpu和tetherin在细胞膜内相互作用。我们还表明，tetherin一直在迅速发展，并可能被置于选择性的压力下改变序列。值得注意的是，似乎已经被置于选择性压力下的部分连接蛋白与影响Vpu拮抗作用的位置一致。因此，灵长类动物的进化历史决定了HIV-1 Vpu在现代物种中的有效性。因此，系链蛋白可以对逆转录病毒的跨物种传播施加屏障。
Tetherin/BST-2/CD317 is a recently identified antiviral protein that blocks the release of nascent retrovirus, and other virus, particles from infected cells. An HIV-1 accessory protein, Vpu, acts as an antagonist of tetherin. Here, we show that positive selection is evident in primate tetherin sequences and that HIV-1 Vpu appears to have specifically adapted to antagonize variants of tetherin found in humans and chimpanzees. Tetherin variants found in rhesus macaques (rh), African green monkeys (agm) and mice were able to inhibit HIV-1 particle release, but were resistant to antagonism by HIV-1 Vpu. Notably, reciprocal exchange of transmembrane domains between human and monkey tetherins conferred sensitivity and resistance to Vpu, identifying this protein domain as a critical determinant of Vpu function. Indeed, differences between hu-tetherin and rh-tetherin at several positions in the transmembrane domain affected sensitivity to antagonism by Vpu. Two alterations in the hu-tetherin transmembrane domain, that correspond to differences found in rh- and agm-tetherin proteins, were sufficient to render hu-tetherin completely resistant to HIV-1 Vpu. Interestingly, transmembrane and cytoplasmic domain sequences in primate tetherins exhibit variation at numerous codons that is likely the result of positive selection, and some of these changes coincide with determinants of HIV-1 Vpu sensitivity. Overall, these data indicate that tetherin could impose a barrier to viral zoonosis as a consequence of positive selection that has been driven by ancient viral antagonists, and that the HIV-1 Vpu protein has specialized to target the transmembrane domains found in human/chimpanzee tetherin proteins. Tetherin is a cell surface protein that acts as an antiviral defense. It functions by tethering newly assembled HIV-1 particles to the surface of the infected cell, such that the viral particle is unable to depart and disseminate to other, uninfected cells. HIV-1 possesses an antagonist of tetherin, termed Vpu, that abolishes tetherin function. We found that HIV-1 is an effective antagonist of human and chimpanzee variants of tetherin but is unable to antagonize tetherins from two monkey species. Additionally, we found that sequence differences in a portion of the protein that is embedded in cell membranes determined whether or not it could be antagonized by Vpu. Since the Vpu protein is alsi a membrane embedded protein, this result suggests that Vpu and tetherin interact within cell membranes. We also show that tetherin has been evolving rapidly, and has likely been placed under selective pressure to change sequence. Notably, portions of tetherin that appear to have been placed under selective pressure coincide with positions that influence Vpu antagonism. Therefore, the evolutionary history of primates determines the effectiveness of HIV-1 Vpu in modern species. Thus, tetherin could impose a barrier to cross species transmission of retroviruses.
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影响因子：
82.9
作者：
Varthakavi, Vasundhara;Heimann-Nichols, Ellen;Spearman, Paul
通讯作者：
Spearman, Paul
影响因子：
6.7
作者：
Bartee E;McCormack A;Früh K
通讯作者：
Früh K
影响因子：
9.8
作者：
Sawyer SL;Emerman M;Malik HS
通讯作者：
Malik HS
影响因子：
5.4
作者：
Song, BW;Gold, B;Sodroski, J
通讯作者：
Sodroski, J
DOI：
10.1073/pnas.2433165100
发表时间：
2003-12-09
影响因子：
11.1
作者：
Varthakavi, V;Smith, RM;Spearman, P
通讯作者：
Spearman, P