title: Annexin V incorporated into influenza virus particles inhibits gamma interferon signaling and promotes viral replication.
abstract: During the budding process, influenza A viruses (IAVs) incorporate multiple host cell membrane proteins. However, for most of them, their significance in viral morphogenesis and infectivity remains unknown. We demonstrate here that the expression of annexin V (A5) is upregulated at the cell surface upon IAV infection and that a substantial proportion of the protein is present in lipid rafts, the site of virus budding. Western blotting and immunogold analysis of highly purified IAV particles showed the presence of A5 in the virion. Significantly, gamma interferon (IFN-γ)-induced Stat phosphorylation and IFN-γ-induced 10-kDa protein (IP-10) production in macrophage-derived THP-1 cells was inhibited by purified IAV particles. Disruption of the IFN-γ signaling pathway was A5 dependent since downregulation of its expression or its blockage reversed the inhibition and resulted in decreased viral replication in vitro. The functional significance of these results was also observed in vivo. Thus, IAVs can subvert the IFN-γ antiviral immune response by incorporating A5 into their envelope during the budding process.
  
  
  OBJECTIVE
  Many enveloped viruses, including influenza A viruses, bud from the plasma membrane of their host cells and incorporate cellular surface proteins into viral particles. However, for the vast majority of these proteins, only the observation of their incorporation has been reported. We demonstrate here that the host protein annexin V is specifically incorporated into influenza virus particles during the budding process. Importantly, we showed that packaged annexin V counteracted the antiviral activity of gamma interferon in vitro and in vivo. Thus, these results showed that annexin V incorporated in the viral envelope of influenza viruses allow viral escape from immune surveillance. Understanding the role of host incorporated protein into virions may reveal how enveloped RNA viruses hijack the host cell machinery for their own purposes.
authors.affiliation: VirPath, EMR4610 Virologie et Pathologie Humaine, Faculté de Médecine RTH Laennec, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France.
authors.forename: Fatma
authors.initials: F
authors.lastname: Berri
authors.affiliation: VirPath, EMR4610 Virologie et Pathologie Humaine, Faculté de Médecine RTH Laennec, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France.
authors.forename: Ghina
authors.initials: G
authors.lastname: Haffar
authors.affiliation: VirPath, EMR4610 Virologie et Pathologie Humaine, Faculté de Médecine RTH Laennec, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France.
authors.forename: Vuong Ba
authors.initials: VB
authors.lastname: Lê
authors.affiliation: Division of Influenza Viruses and Other Respiratory Viruses, Robert Koch Institute, Berlin, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Sadewasser
authors.affiliation: Division of Influenza Viruses and Other Respiratory Viruses, Robert Koch Institute, Berlin, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Paki
authors.affiliation: VirPath, EMR4610 Virologie et Pathologie Humaine, Faculté de Médecine RTH Laennec, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Lina
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: VirPath, EMR4610 Virologie et Pathologie Humaine, Faculté de Médecine RTH Laennec, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France INRA, Tours, France beatrice.riteau@laposte.net.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Riteau
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D009980:Influenza A virus / Q000235:genetics* / Q000378:metabolism; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D061985:Madin Darby Canine Kidney Cells; D021962:Membrane Microdomains / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000378:metabolism / Q000821:virology; D021381:Protein Transport; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D019562:Viral Load; D014771:Virion / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D057074:Virus Release; D014779:Virus Replication
chemical_list: D017304:Annexin A5; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D050791:STAT Transcription Factors; D007371:Interferon-gamma