title: Influenza A virus strains differ in sensitivity to the antiviral action of Mx-GTPase.
abstract: Interferon-mediated host responses are of great importance for controlling influenza A virus infections. It is well established that the interferon-induced Mx proteins possess powerful antiviral activities toward most influenza viruses. Here we analyzed a range of influenza A virus strains for their sensitivities to murine Mx1 and human MxA proteins and found remarkable differences. Virus strains of avian origin were highly sensitive to Mx1, whereas strains of human origin showed much weaker responses. Artificial reassortments of the viral components in a minireplicon system identified the viral nucleoprotein as the main target structure of Mx1. Interestingly, the recently reconstructed 1918 H1N1 "Spanish flu" virus was much less sensitive than the highly pathogenic avian H5N1 strain A/Vietnam/1203/04 when tested in a minireplicon system. Importantly, the human 1918 virus-based minireplicon system was almost insensitive to inhibition by human MxA, whereas the avian influenza A virus H5N1-derived system was well controlled by MxA. These findings suggest that Mx proteins provide a formidable hurdle that hinders influenza A viruses of avian origin from crossing the species barrier to humans. They further imply that the observed insensitivity of the 1918 virus-based replicon to the antiviral activity of human MxA is a hitherto unrecognized characteristic of the "Spanish flu" virus that may contribute to the high virulence of this unusual pandemic strain.
authors.affiliation: Department of Virology, University of Freiburg, Hermann-Herder-Strasse 11, 79107 Freiburg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Dittmann
authors.forename: Silke
authors.initials: S
authors.lastname: Stertz
authors.forename: Daniel
authors.initials: D
authors.lastname: Grimm
authors.forename: John
authors.initials: J
authors.lastname: Steel
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.forename: Otto
authors.initials: O
authors.lastname: Haller
authors.forename: Georg
authors.initials: G
authors.lastname: Kochs
mesh_terms: D000818:Animals; D002460:Cell Line; D002642:Chick Embryo; D004285:Dogs; D019204:GTP-Binding Proteins / Q000276:immunology*; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000276:immunology*; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics / Q000276:immunology*; D051379:Mice; D064547:Myxovirus Resistance Proteins; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins / Q000276:immunology; D016601:RNA-Binding Proteins / Q000276:immunology; D012324:RNA-Dependent RNA Polymerase / Q000378:metabolism; D016865:Reassortant Viruses / Q000235:genetics / Q000276:immunology; D014758:Viral Core Proteins / Q000276:immunology; D010948:Viral Plaque Assay; D014764:Viral Proteins / Q000378:metabolism; D014774:Virulence; D037521:Virulence Factors / Q000276:immunology
chemical_list: C579071:MX1 protein, human; C579070:Mx1 protein, mouse; D064547:Myxovirus Resistance Proteins; C048842:NP protein, Influenza A virus; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins; D016601:RNA-Binding Proteins; D014758:Viral Core Proteins; D014764:Viral Proteins; D037521:Virulence Factors; D012324:RNA-Dependent RNA Polymerase; D019204:GTP-Binding Proteins