species-specific activity of hiv-1 vpu and positive selection of tetherin transmembrane domain variants导致的hiv - 1的活性vpu和积极的选择tetherin跨膜域变异.pdfVIP

Species-Specific Activity of HIV-1 Vpu and Positive Selection of Tetherin Transmembrane Domain Variants 1 1,2 1 3 3 Matthew W. McNatt , Trinity Zang , Theodora Hatziioannou , Mackenzie Bartlett , Ismael Ben Fofana , Welkin E. Johnson3, Stuart J. D. Neil1¤*, Paul D. Bieniasz1,2* 1 Aaron Diamond AIDS Research Center and The Rockefeller University, New York, New York, United States of America, 2 Howard Hughes Medical Institute, New York, New York, United States of America, 3 Department of Microbiology and Molecular Genetics, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts, United States of America Abstract 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, th