title: Tetherin Sensitivity of Influenza A Viruses Is Strain Specific: Role of Hemagglutinin and Neuraminidase.
abstract: The expression of the antiviral host cell factor tetherin is induced by interferon and can inhibit the release of enveloped viruses from infected cells. The Vpu protein of HIV-1 antagonizes the antiviral activity of tetherin, and tetherin antagonists with Vpu-like activity have been identified in other viruses. In contrast, it is incompletely understood whether tetherin inhibits influenza A virus (FLUAV) release and whether FLUAV encodes tetherin antagonists. Here, we show that release of several laboratory-adapted FLUAV strains and a seasonal FLUAV strain is inhibited by tetherin, while pandemic FLUAV A/Hamburg/4/2009 is resistant. Studies with a virus-like particle system and analysis of reassortant viruses provided evidence that the viral hemagglutinin (HA) is an important determinant of tetherin antagonism but requires the presence of its cognate neuraminidase (NA) to inhibit tetherin. Finally, tetherin antagonism by FLUAV was dependent on the virion context, since retrovirus release from tetherin-positive cells was not rescued, and correlated with an HA- and NA-dependent reduction in tetherin expression. In sum, our study identifies HA and NA proteins of certain pandemic FLUAV as tetherin antagonists, which has important implications for understanding FLUAV pathogenesis.
  
  
  OBJECTIVE
  Influenza A virus (FLUAV) infection is responsible for substantial global morbidity and mortality, and understanding how the virus evades the immune defenses of the host may uncover novel targets for antiviral intervention. Tetherin is an antiviral effector molecule of the innate immune system which can contribute to control of viral invasion. However, it has been unclear whether FLUAV is inhibited by tetherin and whether these viruses encode tetherin-antagonizing proteins. Our observation that several pandemic FLUAV strains can counteract tetherin via their HA and NA proteins identifies these proteins as novel tetherin antagonists and indicates that HA/NA-dependent inactivation of innate defenses may contribute to the efficient spread of pandemic FLUAV.
authors.affiliation: Infection Biology Unit, German Primate Center, Göttingen, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Gnirß
authors.affiliation: Infection Biology Unit, German Primate Center, Göttingen, Germany.
authors.forename: Pawel
authors.initials: P
authors.lastname: Zmora
authors.affiliation: Infection Biology Unit, German Primate Center, Göttingen, Germany.
authors.forename: Paulina
authors.initials: P
authors.lastname: Blazejewska
authors.affiliation: Infection Biology Unit, German Primate Center, Göttingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Winkler
authors.affiliation: Infection Biology Unit, German Primate Center, Göttingen, Germany.
authors.forename: Anika
authors.initials: A
authors.lastname: Lins
authors.affiliation: Infection Biology Unit, German Primate Center, Göttingen, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Nehlmeier
authors.affiliation: Infection Biology Unit, German Primate Center, Göttingen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Gärtner
authors.affiliation: Infection Biology Unit, German Primate Center, Göttingen, Germany.
authors.forename: Anna-Sophie
authors.initials: AS
authors.lastname: Moldenhauer
authors.affiliation: Infection Biology Unit, German Primate Center, Göttingen, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Hofmann-Winkler
authors.affiliation: Division of Influenza Viruses and other Respiratory Viruses, Robert Koch Institute, Berlin, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Wolff
authors.affiliation: Institute of Virology, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Munich, Germany Institute of Medical Virology and Epidemiology of Viral Diseases, University Clinic Tübingen, Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schindler
authors.affiliation: Infection Biology Unit, German Primate Center, Göttingen, Germany spoehlmann@dpz.eu.
authors.forename: Stefan
authors.identifier: http://orcid.org/0000-0001-6086-9136
authors.initials: S
authors.lastname: Pöhlmann
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D057809:HEK293 Cells; D015497:HIV-1 / Q000235:genetics / Q000276:immunology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000276:immunology*; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000276:immunology*; D053122:Influenza A Virus, H3N2 Subtype / Q000235:genetics / Q000276:immunology*; D009439:Neuraminidase / Q000235:genetics / Q000276:immunology*; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000276:immunology; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
chemical_list: D015703:Antigens, CD; D058851:GPI-Linked Proteins; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D054298:Human Immunodeficiency Virus Proteins; D009439:Neuraminidase; D054334:Viral Regulatory and Accessory Proteins; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C483468:hemagglutinin, human influenza A virus; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins