title: Vpu-Mediated Counteraction of Tetherin Is a Major Determinant of HIV-1 Interferon Resistance.
abstract: Human immunodeficiency virus type 1 (HIV-1) groups M, N, O, and P are the result of independent zoonotic transmissions of simian immunodeficiency viruses (SIVs) infecting great apes in Africa. Among these, only Vpu proteins of pandemic HIV-1 group M strains evolved potent activity against the restriction factor tetherin, which inhibits virus release from infected cells. Thus, effective Vpu-mediated tetherin antagonism may have been a prerequisite for the global spread of HIV-1. To determine whether this particular function enhances primary HIV-1 replication and interferon resistance, we introduced mutations into the vpu genes of HIV-1 group M and N strains to specifically disrupt their ability to antagonize tetherin, but not other Vpu functions, such as degradation of CD4, down-modulation of CD1d and NTB-A, and suppression of NF-κB activity. Lack of particular human-specific adaptations reduced the ability of HIV-1 group M Vpu proteins to enhance virus production and release from primary CD4(+) T cells at high levels of type I interferon (IFN) from about 5-fold to 2-fold. Interestingly, transmitted founder HIV-1 strains exhibited higher virion release capacity than chronic control HIV-1 strains irrespective of Vpu function, and group M viruses produced higher levels of cell-free virions than an N group HIV-1 strain. Thus, efficient virus release from infected cells seems to play an important role in the spread of HIV-1 in the human population and requires a fully functional Vpu protein that counteracts human tetherin.
  
  
  
  Understanding which human-specific adaptations allowed HIV-1 to cause the AIDS pandemic is of great importance. One feature that distinguishes pandemic HIV-1 group M strains from nonpandemic or rare group O, N, and P viruses is the acquisition of mutations in the accessory Vpu protein that confer potent activity against human tetherin. Adaptation was required because human tetherin has a deletion that renders it resistant to the Nef protein used by the SIV precursor of HIV-1 to antagonize this antiviral factor. It has been suggested that these adaptations in Vpu were critical for the effective spread of HIV-1 M strains, but direct evidence has been lacking. Here, we show that these changes in Vpu significantly enhance virus replication and release in human CD4(+) T cells, particularly in the presence of IFN, thus supporting an important role in the spread of pandemic HIV-1.
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
authors.forename: Dorota
authors.initials: D
authors.lastname: Kmiec
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Shilpa S
authors.initials: SS
authors.lastname: Iyer
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Stürzel
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sauter
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA Department of Microbiology, Perelman School of Medicine, 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 / Q000276:immunology / Q000821:virology; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors; D015497:HIV-1 / Q000276:immunology* / Q000472:pathogenicity*; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D057131:Immune Evasion; D007372:Interferons / Q000276:immunology*; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / 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; D007372:Interferons; 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