title: Efficient Vpu-Mediated Tetherin Antagonism by an HIV-1 Group O Strain.
abstract: Simian immunodeficiency viruses (SIVs) use their Nef proteins to counteract the restriction factor tetherin. However, a deletion in human tetherin prevents antagonism by the Nef proteins of SIVcpz and SIVgor, which represent the ape precursors of human immunodeficiency virus type 1 (HIV-1). To promote virus release from infected cells, pandemic HIV-1 group M strains evolved Vpu as a tetherin antagonist, while the Nef protein of less widespread HIV-1 group O strains acquired the ability to target a region adjacent to this deletion. In this study, we identified an unusual HIV-1 group O strain (RBF206) that evolved Vpu as an effective antagonist of human tetherin. While both RBF206 Vpu and Nef exert anti-tetherin activity in transient-transfection assays, mainly Vpu promotes RBF206 release in infected CD4+T cells. Although mutations distinct from the adaptive changes observed in group M Vpus (M-Vpus) were critical for the acquisition of its anti-tetherin activity, RBF206 O-Vpu potently suppresses NF-κB activation and reduces CD4 cell surface expression. Interestingly, RBF206 Vpu counteracts tetherin in a largely species-independent manner, degrading both the long and short isoforms of human tetherin. Downmodulation of CD4, but not counteraction of tetherin, by RBF206 Vpu was dependent on the cellular ubiquitin ligase machinery. Our data present the first example of an HIV-1 group O Vpu that efficiently antagonizes human tetherin and suggest that counteraction by O-Nefs may be suboptimal.IMPORTANCEPrevious studies showed that HIV-1 groups M and O evolved two alternative strategies to counteract the human ortholog of the restriction factor tetherin. While HIV-1 group M switched from Nef to Vpu due to a deletion in the cytoplasmic domain of human tetherin, HIV-1 group O, which lacks Vpu-mediated anti-tetherin activity, acquired a Nef protein that is able to target a region adjacent to the deletion. Here we report an unusual exception, identifying a strain of HIV-1 group O (RBF206) whose Vpu protein evolved an effective antagonism of human tetherin. Interestingly, the adaptive changes in RBF206 Vpu are distinct from those found in M-Vpus and mediate efficient counteraction of both the long and short isoforms of this restriction factor. Our results further illustrate the enormous flexibility of HIV-1 in counteracting human defense mechanisms.
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Mack
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Starz
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sauter
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Langer
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Frederic
authors.initials: F
authors.lastname: Bibollet-Ruche
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Gerald H
authors.initials: GH
authors.lastname: Learn
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Stürzel
authors.affiliation: Laboratoire de Virologie, CHU Charles Nicolle, Rouen, France.|EA 2656 GRAM Université de Rouen, Rouen, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Leoz
authors.affiliation: Laboratoire de Virologie, CHU Charles Nicolle, Rouen, France.|EA 2656 GRAM Université de Rouen, Rouen, France.|Laboratoire associé au Centre National de Référence du VIH, CHU Charles Nicolle, Rouen, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Plantier
authors.affiliation: Department of Structural Immunology, Institute of Innate Immunity, University of Bonn, Bonn, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Geyer
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany frank.kirchhoff@uni-ulm.de.
authors.forename: Frank
authors.initials: F
authors.lastname: Kirchhoff
mesh_terms: D015703:Antigens, CD; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002460:Cell Line; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors; D015497:HIV-1 / Q000276:immunology* / Q000502:physiology*; D054884:Host-Pathogen Interactions; D054298:Human Immunodeficiency Virus Proteins / Q000378:metabolism*; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism*; D057074:Virus Release; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
chemical_list: D015703:Antigens, CD; D058851:GPI-Linked Proteins; D054298:Human Immunodeficiency Virus Proteins; D016328:NF-kappa B; 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
keywords: HIV-1 group O; Vpu; antagonism; tetherin