title: Reacquisition of Nef-mediated tetherin antagonism in a single in vivo passage of HIV-1 through its original chimpanzee host.
abstract: The interferon-induced host restriction factor tetherin poses a barrier for SIV transmission from primates to humans. After cross-species transmission, the chimpanzee precursor of pandemic HIV-1 switched from the accessory protein Nef to Vpu to effectively counteract human tetherin. As we report here, the experimental reintroduction of HIV-1 into its original chimpanzee host resulted in a virus that can use both Vpu and Nef to antagonize chimpanzee tetherin. Functional analyses demonstrated that alterations in and near the highly conserved ExxxLL motif in the C-terminal loop of Nef were critical for the reacquisition of antitetherin activity. Strikingly, just two amino acid changes allowed HIV-1 Nef to counteract chimpanzee tetherin and promote virus release. Our data demonstrate that primate lentiviruses can reacquire lost accessory gene functions during a single in vivo passage and suggest that other functional constraints keep Nef ready to regain antitetherin activity.
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
authors.forename: Nicola
authors.initials: N
authors.lastname: Götz
authors.forename: Daniel
authors.initials: D
authors.lastname: Sauter
authors.forename: Shariq M
authors.initials: SM
authors.lastname: Usmani
authors.forename: Joëlle V
authors.initials: JV
authors.lastname: Fritz
authors.forename: Christine
authors.initials: C
authors.lastname: Goffinet
authors.forename: Anke
authors.initials: A
authors.lastname: Heigele
authors.forename: Matthias
authors.initials: M
authors.lastname: Geyer
authors.forename: Frederic
authors.initials: F
authors.lastname: Bibollet-Ruche
authors.forename: Gerald H
authors.initials: GH
authors.lastname: Learn
authors.forename: Oliver T
authors.initials: OT
authors.lastname: Fackler
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.forename: Frank
authors.initials: F
authors.lastname: Kirchhoff
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D004195:Disease Models, Animal; D015497:HIV-1 / Q000254:growth & development / Q000276:immunology*; D054298:Human Immunodeficiency Virus Proteins / Q000378:metabolism*; D006801:Humans; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D002679:Pan troglodytes; D018419:Primate Diseases / Q000276:immunology* / Q000821:virology; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism*; D037521:Virulence Factors / Q000378:metabolism*; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*; D000086082:Viroporin Proteins
chemical_list: D015703:Antigens, CD; D054298:Human Immunodeficiency Virus Proteins; D050505:Mutant Proteins; D054334:Viral Regulatory and Accessory Proteins; D037521:Virulence Factors; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins