title: Nef proteins of epidemic HIV-1 group O strains antagonize human tetherin.
abstract: Most simian immunodeficiency viruses use their Nef protein to antagonize the host restriction factor tetherin. A deletion in human tetherin confers Nef resistance, representing a hurdle to successful zoonotic transmission. HIV-1 group M evolved to utilize the viral protein U (Vpu) to counteract tetherin. Although HIV-1 group O has spread epidemically in humans, it has not evolved a Vpu-based tetherin antagonism. Here we show that HIV-1 group O Nef targets a region adjacent to this deletion to inhibit transport of human tetherin to the cell surface, enhances virion release, and increases viral resistance to inhibition by interferon-&#945;. The Nef protein of the inferred common ancestor of group O viruses is also active against human tetherin. Thus, Nef-mediated antagonism of human tetherin evolved prior to the spread of HIV-1 group O and likely facilitated secondary virus transmission. Our results may explain the epidemic spread of HIV-1 group O.
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
authors.forename: Silvia F
authors.initials: SF
authors.lastname: Kluge
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Mack
authors.affiliation: Departments of Medicine and Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Shilpa S
authors.initials: SS
authors.lastname: Iyer
authors.affiliation: Department of Infectious Diseases, Integrative Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: François M
authors.initials: FM
authors.lastname: Pujol
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Heigele
authors.affiliation: Departments of Medicine and Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Gerald H
authors.initials: GH
authors.lastname: Learn
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
authors.forename: Shariq M
authors.initials: SM
authors.lastname: Usmani
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sauter
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Joas
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Hotter
authors.affiliation: Departments of Medicine and Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Frederic
authors.initials: F
authors.lastname: Bibollet-Ruche
authors.affiliation: Institute of Evolutionary Biology, University of Edinburgh, Edinburgh EH9 3JT, UK.
authors.forename: Lindsey J
authors.initials: LJ
authors.lastname: Plenderleith
authors.affiliation: UMI233, TransVIHMI, Institut de Recherche pour le Développement (IRD) and Université Montpellier, Montpellier 34394, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Peeters
authors.affiliation: Group Physical Biochemistry, Center of Advanced European Studies and Research, 53175 Bonn, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Geyer
authors.affiliation: Institute of Evolutionary Biology, University of Edinburgh, Edinburgh EH9 3JT, UK.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Sharp
authors.affiliation: Department of Infectious Diseases, Integrative Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Oliver T
authors.initials: OT
authors.lastname: Fackler
authors.affiliation: Departments of Medicine and Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. Electronic address: bhahn@upenn.edu.
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany. Electronic address: frank.kirchhoff@uni-ulm.de.
authors.forename: Frank
authors.initials: F
authors.lastname: Kirchhoff
mesh_terms: D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D045744:Cell Line, Tumor; D004705:Endocytosis; D019143:Evolution, Molecular; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D015497:HIV-1 / Q000145:classification / Q000472:pathogenicity*; D006801:Humans; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017421:Sequence Analysis; D017384:Sequence Deletion; D014771:Virion / Q000235:genetics / Q000378:metabolism; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*; D000074010:Bone Marrow Stromal Antigen 2
chemical_list: D015703:Antigens, CD; D058851:GPI-Linked Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2