title: Species-specific activity of HIV-1 Vpu and positive selection of tetherin transmembrane domain variants.
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, 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.
authors.affiliation: Aaron Diamond AIDS Research Center and The Rockefeller University, New York, New York, United States of America.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: McNatt
authors.forename: Trinity
authors.initials: T
authors.lastname: Zang
authors.forename: Theodora
authors.initials: T
authors.lastname: Hatziioannou
authors.forename: Mackenzie
authors.initials: M
authors.lastname: Bartlett
authors.forename: Ismael Ben
authors.initials: IB
authors.lastname: Fofana
authors.forename: Welkin E
authors.initials: WE
authors.lastname: Johnson
authors.forename: Stuart J D
authors.initials: SJ
authors.lastname: Neil
authors.forename: Paul D
authors.initials: PD
authors.lastname: Bieniasz
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002522:Chlorocebus aethiops; D019143:Evolution, Molecular; D058851:GPI-Linked Proteins; D054298:Human Immunodeficiency Virus Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D008253:Macaca mulatta; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D002679:Pan troglodytes; D011110:Polymorphism, Genetic; D017434:Protein Structure, Tertiary / Q000235:genetics*; D012641:Selection, Genetic; D013045:Species Specificity; D054334:Viral Regulatory and Accessory Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D014771:Virion / Q000378:metabolism; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
chemical_list: D015703:Antigens, CD; D058851:GPI-Linked Proteins; D054298:Human Immunodeficiency Virus Proteins; D008562:Membrane Glycoproteins; D054334:Viral Regulatory and Accessory Proteins; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins