1887

Abstract

The non-structural (NS1) protein of influenza A viruses is a non-essential virulence factor that has multiple accessory functions during viral infection. In recent years, the major role ascribed to NS1 has been its inhibition of host immune responses, especially the limitation of both interferon (IFN) production and the antiviral effects of IFN-induced proteins, such as dsRNA-dependent protein kinase R (PKR) and 2'5'-oligoadenylate synthetase (OAS)/RNase L. However, it is clear that NS1 also acts directly to modulate other important aspects of the virus replication cycle, including viral RNA replication, viral protein synthesis, and general host-cell physiology. Here, we review the current literature on this remarkably multifunctional viral protein. In the first part of this article, we summarize the basic biochemistry of NS1, in particular its synthesis, structure, and intracellular localization. We then discuss the various roles NS1 has in regulating viral replication mechanisms, host innate/adaptive immune responses, and cellular signalling pathways. We focus on the NS1–RNA and NS1–protein interactions that are fundamental to these processes, and highlight apparent strain-specific ways in which different NS1 proteins may act. In this regard, the contributions of certain NS1 functions to the pathogenicity of human and animal influenza A viruses are also discussed. Finally, we outline practical applications that future studies on NS1 may lead to, including the rational design and manufacture of influenza vaccines, the development of novel antiviral drugs, and the use of oncolytic influenza A viruses as potential anti-cancer agents.

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2008-10-01
2024-03-19
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References

  1. Alonso-Caplen F. V., Krug R. M. 1991; Regulation of the extent of splicing of influenza virus NS1 mRNA: role of the rates of splicing and of the nucleocytoplasmic transport of NS1 mRNA. Mol Cell Biol 11:1092–1098
    [Google Scholar]
  2. Alonso-Caplen F. V., Nemeroff M. E., Qiu Y., Krug R. M. 1992; Nucleocytoplasmic transport: the influenza virus NS1 protein regulates the transport of spliced NS2 mRNA and its precursor NS1 mRNA. Genes Dev 6:255–267 [CrossRef]
    [Google Scholar]
  3. Aragon T., de la Luna S., Novoa I., Carrasco L., Ortin J., Nieto A. 2000; Eukaryotic translation initiation factor 4GI is a cellular target for NS1 protein, a translational activator of influenza virus. Mol Cell Biol 20:6259–6268 [CrossRef]
    [Google Scholar]
  4. Barker W. H., Mullooly J. P. 1982; Pneumonia and influenza deaths during epidemics: implications for prevention. Arch Intern Med 142:85–89 [CrossRef]
    [Google Scholar]
  5. Baskin C. R., Bielefeldt-Ohmann H., Garcia-Sastre A., Tumpey T. M., Van Hoeven N., Carter V. S., Thomas M. J., Proll S., Solorzano A.other authors 2007; Functional genomic and serological analysis of the protective immune response resulting from vaccination of macaques with an NS1-truncated influenza virus. J Virol 81:11817–11827 [CrossRef]
    [Google Scholar]
  6. Basler C. F., Reid A. H., Dybing J. K., Janczewski T. A., Fanning T. G., Zheng H., Salvatore M., Perdue M. L., Swayne D. E.other authors 2001; Sequence of the 1918 pandemic influenza virus nonstructural gene (NS) segment and characterization of recombinant viruses bearing the 1918 NS genes. Proc Natl Acad Sci U S A 98:2746–2751 [CrossRef]
    [Google Scholar]
  7. Bergmann M., Garcia-Sastre A., Carnero E., Pehamberger H., Wolff K., Palese P., Muster T. 2000; Influenza virus NS1 protein counteracts PKR-mediated inhibition of replication. J Virol 74:6203–6206 [CrossRef]
    [Google Scholar]
  8. Bergmann M., Romirer I., Sachet M., Fleischhacker R., Garcia-Sastre A., Palese P., Wolff K., Pehamberger H., Jakesz R., Muster T. 2001; A genetically engineered influenza A virus with ras -dependent oncolytic properties. Cancer Res 61:8188–8193
    [Google Scholar]
  9. Bornholdt Z. A., Prasad B. V. 2006; X-ray structure of influenza virus NS1 effector domain. Nat Struct Mol Biol 13:559–560 [CrossRef]
    [Google Scholar]
  10. Bucher E., Hemmes H., de Haan P., Goldbach R., Prins M. 2004; The influenza A virus NS1 protein binds small interfering RNAs and suppresses RNA silencing in plants. J Gen Virol 85:983–991 [CrossRef]
    [Google Scholar]
  11. Burgui I., Aragon T., Ortin J., Nieto A. 2003; PABP1 and eIF4GI associate with influenza virus NS1 protein in viral mRNA translation initiation complexes. J Gen Virol 84:3263–3274 [CrossRef]
    [Google Scholar]
  12. Castiglioni P., Hall D. S., Jacovetty E. L., Ingulli E., Zanetti M. 2008; Protection against influenza A virus by memory CD8 T cells requires reactivation by bone marrow-derived dendritic cells. J Immunol 180:4956–4964 [CrossRef]
    [Google Scholar]
  13. Cauthen A. N., Swayne D. E., Sekellick M. J., Marcus P. I., Suarez D. L. 2007; Amelioration of influenza virus pathogenesis in chickens attributed to the enhanced interferon-inducing capacity of a virus with a truncated NS1 gene. J Virol 81:1838–1847 [CrossRef]
    [Google Scholar]
  14. Chen Z., Li Y., Krug R. M. 1999; Influenza A virus NS1 protein targets poly(A)-binding protein II of the cellular 3′-end processing machinery. EMBO J 18:2273–2283 [CrossRef]
    [Google Scholar]
  15. Cheung C. Y., Poon L. L., Lau A. S., Luk W., Lau Y. L., Shortridge K. F., Gordon S., Guan Y., Peiris J. S. 2002; Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease?. Lancet 360:1831–1837 [CrossRef]
    [Google Scholar]
  16. Chien C. Y., Tejero R., Huang Y., Zimmerman D. E., Rios C. B., Krug R. M., Montelione G. T. 1997; A novel RNA-binding motif in influenza A virus non-structural protein 1. Nat Struct Biol 4:891–895 [CrossRef]
    [Google Scholar]
  17. Chien C. Y., Xu Y., Xiao R., Aramini J. M., Sahasrabudhe P. V., Krug R. M., Montelione G. T. 2004; Biophysical characterization of the complex between double-stranded RNA and the N-terminal domain of the NS1 protein from influenza A virus: evidence for a novel RNA-binding mode. Biochemistry 43:1950–1962 [CrossRef]
    [Google Scholar]
  18. de la Luna S., Fortes P., Beloso A., Ortin J. 1995; Influenza virus NS1 protein enhances the rate of translation initiation of viral mRNAs. J Virol 69:2427–2433
    [Google Scholar]
  19. Delgadillo M. O., Saenz P., Salvador B., Garcia J. A., Simon-Mateo C. 2004; Human influenza virus NS1 protein enhances viral pathogenicity and acts as an RNA silencing suppressor in plants. J Gen Virol 85:993–999 [CrossRef]
    [Google Scholar]
  20. Dittmann J., Stertz S., Grimm D., Steel J., Garcia-Sastre A., Haller O., Kochs G. 2008; Influenza A virus strains differ in sensitivity to the antiviral action of Mx-GTPase. J Virol 82:3624–3631 [CrossRef]
    [Google Scholar]
  21. Donelan N. R., Basler C. F., Garcia-Sastre A. 2003; A recombinant influenza A virus expressing an RNA-binding-defective NS1 protein induces high levels of beta interferon and is attenuated in mice. J Virol 77:13257–13266 [CrossRef]
    [Google Scholar]
  22. Efferson C. L., Tsuda N., Kawano K., Nistal-Villan E., Sellappan S., Yu D., Murray J. L., Garcia-Sastre A., Ioannides C. G. 2006; Prostate tumor cells infected with a recombinant influenza virus expressing a truncated NS1 protein activate cytolytic CD8+ cells to recognize noninfected tumor cells. J Virol 80:383–394 [CrossRef]
    [Google Scholar]
  23. Egorov A., Brandt S., Sereinig S., Romanova J., Ferko B., Katinger D., Grassauer A., Alexandrova G., Katinger H., Muster T. 1998; Transfectant influenza A viruses with long deletions in the NS1 protein grow efficiently in Vero cells. J Virol 72:6437–6441
    [Google Scholar]
  24. Ehrhardt C., Marjuki H., Wolff T., Nurnberg B., Planz O., Pleschka S., Ludwig S. 2006; Bivalent role of the phosphatidylinositol-3-kinase (PI3K) during influenza virus infection and host cell defence. Cell Microbiol 8:1336–1348 [CrossRef]
    [Google Scholar]
  25. Ehrhardt C., Wolff T., Pleschka S., Planz O., Beermann W., Bode J. G., Schmolke M., Ludwig S. 2007; Influenza A virus NS1 protein activates the PI3K/Akt pathway to mediate antiapoptotic signaling responses. J Virol 81:3058–3067 [CrossRef]
    [Google Scholar]
  26. Enami M., Enami K. 2000; Characterization of influenza virus NS1 protein by using a novel helper-virus-free reverse genetic system. J Virol 74:5556–5561 [CrossRef]
    [Google Scholar]
  27. Enami K., Sato T. A., Nakada S., Enami M. 1994; Influenza virus NS1 protein stimulates translation of the M1 protein. J Virol 68:1432–1437
    [Google Scholar]
  28. Falcon A. M., Fortes P., Marion R. M., Beloso A., Ortin J. 1999; Interaction of influenza virus NS1 protein and the human homologue of Staufen in vivo and in vitro . Nucleic Acids Res 27:2241–2247 [CrossRef]
    [Google Scholar]
  29. Falcon A. M., Marion R. M., Zurcher T., Gomez P., Portela A., Nieto A., Ortin J. 2004; Defective RNA replication and late gene expression in temperature-sensitive influenza viruses expressing deleted forms of the NS1 protein. J Virol 78:3880–3888 [CrossRef]
    [Google Scholar]
  30. Falcon A. M., Fernandez-Sesma A., Nakaya Y., Moran T. M., Ortin J., Garcia-Sastre A. 2005; Attenuation and immunogenicity in mice of temperature-sensitive influenza viruses expressing truncated NS1 proteins. J Gen Virol 86:2817–2821 [CrossRef]
    [Google Scholar]
  31. Feigenblum D., Schneider R. J. 1993; Modification of eukaryotic initiation factor 4F during infection by influenza virus. J Virol 67:3027–3035
    [Google Scholar]
  32. Ferko B., Stasakova J., Romanova J., Kittel C., Sereinig S., Katinger H., Egorov A. 2004; Immunogenicity and protection efficacy of replication-deficient influenza A viruses with altered NS1 genes. J Virol 78:13037–13045 [CrossRef]
    [Google Scholar]
  33. Fernandez-Sesma A., Marukian S., Ebersole B. J., Kaminski D., Park M. S., Yuen T., Sealfon S. C., Garcia-Sastre A., Moran T. M. 2006; Influenza virus evades innate and adaptive immunity via the NS1 protein. J Virol 80:6295–6304 [CrossRef]
    [Google Scholar]
  34. Finkelstein D. B., Mukatira S., Mehta P. K., Obenauer J. C., Su X., Webster R. G., Naeve C. W. 2007; Persistent host markers in pandemic and H5N1 influenza viruses. J Virol 81:10292–10299 [CrossRef]
    [Google Scholar]
  35. Fortes P., Beloso A., Ortin J. 1994; Influenza virus NS1 protein inhibits pre-mRNA splicing and blocks mRNA nucleocytoplasmic transport. EMBO J 13:704–712
    [Google Scholar]
  36. Fortes P., Lamond A. I., Ortin J. 1995; Influenza virus NS1 protein alters the subnuclear localization of cellular splicing components. J Gen Virol 76:1001–1007 [CrossRef]
    [Google Scholar]
  37. Fukao T., Koyasu S. 2003; PI3K and negative regulation of TLR signaling. Trends Immunol 24:358–363 [CrossRef]
    [Google Scholar]
  38. Garaigorta U., Ortin J. 2007; Mutation analysis of a recombinant NS replicon shows that influenza virus NS1 protein blocks the splicing and nucleo-cytoplasmic transport of its own viral mRNA. Nucleic Acids Res 35:4573–4582 [CrossRef]
    [Google Scholar]
  39. Garaigorta U., Falcon A. M., Ortin J. 2005; Genetic analysis of influenza virus NS1 gene: a temperature-sensitive mutant shows defective formation of virus particles. J Virol 79:15246–15257 [CrossRef]
    [Google Scholar]
  40. Garcia M. A., Gil J., Ventoso I., Guerra S., Domingo E., Rivas C., Esteban M. 2006; Impact of protein kinase PKR in cell biology: from antiviral to antiproliferative action. Microbiol Mol Biol Rev 70:1032–1060 [CrossRef]
    [Google Scholar]
  41. Garcia-Sastre A., Egorov A., Matassov D., Brandt S., Levy D. E., Durbin J. E., Palese P., Muster T. 1998; Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems. Virology 252:324–330 [CrossRef]
    [Google Scholar]
  42. Garfinkel M. S., Katze M. G. 1993; Translational control by influenza virus. Selective translation is mediated by sequences within the viral mRNA 5′-untranslated region. J Biol Chem 268:22223–22226
    [Google Scholar]
  43. Geiss G. K., Salvatore M., Tumpey T. M., Carter V. S., Wang X., Basler C. F., Taubenberger J. K., Bumgarner R. E., Palese P.other authors 2002; Cellular transcriptional profiling in influenza A virus-infected lung epithelial cells: the role of the nonstructural NS1 protein in the evasion of the host innate defense and its potential contribution to pandemic influenza. Proc Natl Acad Sci U S A 99:10736–10741 [CrossRef]
    [Google Scholar]
  44. Gharbi S. I., Zvelebil M. J., Shuttleworth S. J., Hancox T., Saghir N., Timms J. F., Waterfield M. D. 2007; Exploring the specificity of the PI3K family inhibitor LY294002. Biochem J 404:15–21 [CrossRef]
    [Google Scholar]
  45. Greenspan D., Palese P., Krystal M. 1988; Two nuclear location signals in the influenza virus NS1 nonstructural protein. J Virol 62:3020–3026
    [Google Scholar]
  46. Grimm D., Staeheli P., Hufbauer M., Koerner I., Martinez-Sobrido L., Solorzano A., Garcia-Sastre A., Haller O., Kochs G. 2007; Replication fitness determines high virulence of influenza A virus in mice carrying functional Mx1 resistance gene. Proc Natl Acad Sci U S A 104:6806–6811 [CrossRef]
    [Google Scholar]
  47. Guo Z., Chen L. M., Zeng H., Gomez J. A., Plowden J., Fujita T., Katz J. M., Donis R. O., Sambhara S. 2007; NS1 protein of influenza A virus inhibits the function of intracytoplasmic pathogen sensor, RIG-I. Am J Respir Cell Mol Biol 36:263–269 [CrossRef]
    [Google Scholar]
  48. Hale B. G., Jackson D., Chen Y. H., Lamb R. A., Randall R. E. 2006; Influenza A virus NS1 protein binds p85 β and activates phosphatidylinositol-3-kinase signaling. Proc Natl Acad Sci U S A 103:14194–14199 [CrossRef]
    [Google Scholar]
  49. Hale B. G., Barclay W. S., Randall R. E., Russell R. J. 2008a; Structure of an avian influenza A virus NS1 protein effector domain. Virology 378:1–5 [CrossRef]
    [Google Scholar]
  50. Hale B. G., Batty I. H., Downes C. P., Randall R. E. 2008b; Binding of influenza A virus NS1 protein to the inter-SH2 domain of p85 suggests a novel mechanism for phosphoinositide 3-kinase activation. J Biol Chem 283:1372–1380 [CrossRef]
    [Google Scholar]
  51. Hatada E., Fukuda R. 1992; Binding of influenza A virus NS1 protein to dsRNA in vitro . J Gen Virol 73:3325–3329 [CrossRef]
    [Google Scholar]
  52. Hatada E., Hasegawa M., Shimizu K., Hatanaka M., Fukuda R. 1990; Analysis of influenza A virus temperature-sensitive mutants with mutations in RNA segment 8. J Gen Virol 71:1283–1292 [CrossRef]
    [Google Scholar]
  53. Hatada E., Saito S., Okishio N., Fukuda R. 1997; Binding of the influenza virus NS1 protein to model genome RNAs. J Gen Virol 78:1059–1063
    [Google Scholar]
  54. Hatada E., Saito S., Fukuda R. 1999; Mutant influenza viruses with a defective NS1 protein cannot block the activation of PKR in infected cells. J Virol 73:2425–2433
    [Google Scholar]
  55. Hawkins P. T., Anderson K. E., Davidson K., Stephens L. R. 2006; Signalling through Class I PI3Ks in mammalian cells. Biochem Soc Trans 34:647–662 [CrossRef]
    [Google Scholar]
  56. Hayman A., Comely S., Lackenby A., Murphy S., McCauley J., Goodbourn S., Barclay W. 2006; Variation in the ability of human influenza A viruses to induce and inhibit the IFN- β pathway. Virology 347:52–64 [CrossRef]
    [Google Scholar]
  57. Hayman A., Comely S., Lackenby A., Hartgroves L. C., Goodbourn S., McCauley J. W., Barclay W. S. 2007; NS1 proteins of avian influenza A viruses can act as antagonists of the human alpha/beta interferon response. J Virol 81:2318–2327 [CrossRef]
    [Google Scholar]
  58. Heikkinen L. S., Kazlauskas A., Melen K., Wagner R., Ziegler T., Julkunen I., Saksela K. 2008; Avian and 1918 Spanish influenza a virus NS1 proteins bind to Crk/CrkL Src homology 3 domains to activate host cell signaling. J Biol Chem 283:5719–5727
    [Google Scholar]
  59. Hyland L., Webby R., Sandbulte M. R., Clarke B., Hou S. 2006; Influenza virus NS1 protein protects against lymphohematopoietic pathogenesis in an in vivo mouse model. Virology 349:156–163 [CrossRef]
    [Google Scholar]
  60. Inglis S. C., Barrett T., Brown C. M., Almond J. W. 1979; The smallest genome RNA segment of influenza virus contains two genes that may overlap. Proc Natl Acad Sci U S A 76:3790–3794 [CrossRef]
    [Google Scholar]
  61. Jackson D., Hossain M. J., Hickman D., Perez D. R., Lamb R. A. 2008; A new influenza virus virulence determinant: the NS1 protein four C-terminal residues modulate pathogenicity. Proc Natl Acad Sci U S A 105:4381–4386 [CrossRef]
    [Google Scholar]
  62. Jiao P., Tian G., Li Y., Deng G., Jiang Y., Liu C., Liu W., Bu Z., Kawaoka Y., Chen H. 2008; A single-amino-acid substitution in the NS1 protein changes the pathogenicity of H5N1 avian influenza viruses in mice. J Virol 82:1146–1154 [CrossRef]
    [Google Scholar]
  63. Kochs G., Garcia-Sastre A., Martinez-Sobrido L. 2007a; Multiple anti-interferon actions of the influenza A virus NS1 protein. J Virol 81:7011–7021 [CrossRef]
    [Google Scholar]
  64. Kochs G., Koerner I., Thiel L., Kothlow S., Kaspers B., Ruggli N., Summerfield A., Pavlovic J., Stech J., Staeheli P. 2007b; Properties of H7N7 influenza A virus strain SC35M lacking interferon antagonist NS1 in mice and chickens. J Gen Virol 88:1403–1409 [CrossRef]
    [Google Scholar]
  65. Kok K. H., Jin D. Y. 2006; Influenza A virus NS1 protein does not suppress RNA interference in mammalian cells. J Gen Virol 87:2639–2644 [CrossRef]
    [Google Scholar]
  66. Krug R. M., Etkind P. R. 1973; Cytoplasmic and nuclear virus-specific proteins in influenza virus-infected MDCK cells. Virology 56:334–348 [CrossRef]
    [Google Scholar]
  67. Kurokawa M., Koyama A. H., Yasuoka S., Adachi A. 1999; Influenza virus overcomes apoptosis by rapid multiplication. Int J Mol Med 3:527–530
    [Google Scholar]
  68. Lam W. Y., Tang J. W., Yeung A. C., Chiu L. C., Sung J. J., Chan P. K. 2008; Avian influenza virus A/HK/483/97(H5N1) NS1 protein induces apoptosis in human airway epithelial cells. J Virol 82:2741–2751 [CrossRef]
    [Google Scholar]
  69. Lamb R. A., Choppin P. W. 1979; Segment 8 of the influenza virus genome is unique in coding for two polypeptides. Proc Natl Acad Sci U S A 76:4908–4912 [CrossRef]
    [Google Scholar]
  70. Lamb R. A., Lai C. J. 1980; Sequence of interrupted and uninterrupted mRNAs and cloned DNA coding for the two overlapping nonstructural proteins of influenza virus. Cell 21:475–485 [CrossRef]
    [Google Scholar]
  71. Lamb R. A., Choppin P. W., Chanock R. M., Lai C. J. 1980; Mapping of the two overlapping genes for polypeptides NS1 and NS2 on RNA segment 8 of influenza virus genome. Proc Natl Acad Sci U S A 77:1857–1861 [CrossRef]
    [Google Scholar]
  72. Li Y., Yamakita Y., Krug R. M. 1998; Regulation of a nuclear export signal by an adjacent inhibitory sequence: the effector domain of the influenza virus NS1 protein. Proc Natl Acad Sci U S A 95:4864–4869 [CrossRef]
    [Google Scholar]
  73. Li Y., Chen Z. Y., Wang W., Baker C. C., Krug R. M. 2001; The 3′-end-processing factor CPSF is required for the splicing of single-intron pre-mRNAs in vivo. RNA 7:920–931 [CrossRef]
    [Google Scholar]
  74. Li W. X., Li H., Lu R., Li F., Dus M., Atkinson P., Brydon E. W., Johnson K. L., Garcia-Sastre A.other authors 2004; Interferon antagonist proteins of influenza and vaccinia viruses are suppressors of RNA silencing. Proc Natl Acad Sci U S A 101:1350–1355 [CrossRef]
    [Google Scholar]
  75. Li S., Min J. Y., Krug R. M., Sen G. C. 2006a; Binding of the influenza A virus NS1 protein to PKR mediates the inhibition of its activation by either PACT or double-stranded RNA. Virology 349:13–21 [CrossRef]
    [Google Scholar]
  76. Li Z., Jiang Y., Jiao P., Wang A., Zhao F., Tian G., Wang X., Yu K., Bu Z., Chen H. 2006b; The NS1 gene contributes to the virulence of H5N1 avian influenza viruses. J Virol 80:11115–11123 [CrossRef]
    [Google Scholar]
  77. Li Y., Anderson D. H., Liu Q., Zhou Y. 2008; Mechanism of influenza A virus NS1 protein interaction with the p85 β , but not the p85 α , subunit of PI3K and upregulation of PI3K activity. J Biol Chem in press
  78. Lipatov A. S., Andreansky S., Webby R. J., Hulse D. J., Rehg J. E., Krauss S., Perez D. R., Doherty P. C., Webster R. G., Sangster M. Y. 2005; Pathogenesis of Hong Kong H5N1 influenza virus NS gene reassortants in mice: the role of cytokines and B- and T-cell responses. J Gen Virol 86:1121–1130 [CrossRef]
    [Google Scholar]
  79. Liu J., Lynch P. A., Chien C. Y., Montelione G. T., Krug R. M., Berman H. M. 1997; Crystal structure of the unique RNA-binding domain of the influenza virus NS1 protein. Nat Struct Biol 4:896–899 [CrossRef]
    [Google Scholar]
  80. Long J. X., Peng D. X., Liu Y. L., Wu Y. T., Liu X. F. 2008; Virulence of H5N1 avian influenza virus enhanced by a 15-nucleotide deletion in the viral nonstructural gene. Virus Genes 36:471–478 [CrossRef]
    [Google Scholar]
  81. Lu Y., Qian X. Y., Krug R. M. 1994; The influenza virus NS1 protein: a novel inhibitor of pre-mRNA splicing. Genes Dev 8:1817–1828 [CrossRef]
    [Google Scholar]
  82. Lu Y., Wambach M., Katze M. G., Krug R. M. 1995; Binding of the influenza virus NS1 protein to double-stranded RNA inhibits the activation of the protein kinase that phosphorylates the elF-2 translation initiation factor. Virology 214:222–228 [CrossRef]
    [Google Scholar]
  83. Ludwig S., Schultz U., Mandler J., Fitch W. M., Scholtissek C. 1991; Phylogenetic relationship of the nonstructural (NS) genes of influenza A viruses. Virology 183:566–577 [CrossRef]
    [Google Scholar]
  84. Ludwig S., Wang X., Ehrhardt C., Zheng H., Donelan N., Planz O., Pleschka S., Garcia-Sastre A., Heins G., Wolff T. 2002; The influenza A virus NS1 protein inhibits activation of Jun N-terminal kinase and AP-1 transcription factors. J Virol 76:11166–11171 [CrossRef]
    [Google Scholar]
  85. Marion R. M., Aragon T., Beloso A., Nieto A., Ortin J. 1997a; The N-terminal half of the influenza virus NS1 protein is sufficient for nuclear retention of mRNA and enhancement of viral mRNA translation. Nucleic Acids Res 25:4271–4277 [CrossRef]
    [Google Scholar]
  86. Marion R. M., Zurcher T., de la Luna S., Ortin J. 1997b; Influenza virus NS1 protein interacts with viral transcription-replication complexes in vivo . J Gen Virol 78:2447–2451
    [Google Scholar]
  87. Matskevich A. A., Moelling K. 2007; Dicer is involved in protection against influenza A virus infection. J Gen Virol 88:2627–2635 [CrossRef]
    [Google Scholar]
  88. Melen K., Kinnunen L., Fagerlund R., Ikonen N., Twu K. Y., Krug R. M., Julkunen I. 2007; Nuclear and nucleolar targeting of influenza A virus NS1 protein: striking differences between different virus subtypes. J Virol 81:5995–6006 [CrossRef]
    [Google Scholar]
  89. Mibayashi M., Martinez-Sobrido L., Loo Y. M., Cardenas W. B., Gale M. Jr, Garcia-Sastre A. 2007; Inhibition of retinoic acid-inducible gene I-mediated induction of beta interferon by the NS1 protein of influenza A virus. J Virol 81:514–524 [CrossRef]
    [Google Scholar]
  90. Min J. Y., Krug R. M. 2006; The primary function of RNA binding by the influenza A virus NS1 protein in infected cells: inhibiting the 2′-5′ oligo (A) synthetase/RNase L pathway. Proc Natl Acad Sci U S A 103:7100–7105 [CrossRef]
    [Google Scholar]
  91. Min J. Y., Li S., Sen G. C., Krug R. M. 2007; A site on the influenza A virus NS1 protein mediates both inhibition of PKR activation and temporal regulation of viral RNA synthesis. Virology 363:236–243 [CrossRef]
    [Google Scholar]
  92. Murayama R., Harada Y., Shibata T., Kuroda K., Hayakawa S., Shimizu K., Tanaka T. 2007; Influenza A virus non-structural protein 1 (NS1) interacts with cellular multifunctional protein nucleolin during infection. Biochem Biophys Res Commun 362:880–885 [CrossRef]
    [Google Scholar]
  93. Muster T., Rajtarova J., Sachet M., Unger H., Fleischhacker R., Romirer I., Grassauer A., Url A., Garcia-Sastre A.other authors 2004; Interferon resistance promotes oncolysis by influenza virus NS1-deletion mutants. Int J Cancer 110:15–21 [CrossRef]
    [Google Scholar]
  94. Nemeroff M. E., Qian X. Y., Krug R. M. 1995; The influenza virus NS1 protein forms multimers in vitro and in vivo . Virology 212:422–428 [CrossRef]
    [Google Scholar]
  95. Nemeroff M. E., Barabino S. M., Li Y., Keller W., Krug R. M. 1998; Influenza virus NS1 protein interacts with the cellular 30 kDa subunit of CPSF and inhibits 3′ end formation of cellular pre-mRNAs. Mol Cell 1:991–1000 [CrossRef]
    [Google Scholar]
  96. Newby C. M., Sabin L., Pekosz A. 2007; The RNA binding domain of influenza A virus NS1 protein affects secretion of tumor necrosis factor alpha, interleukin-6, and interferon in primary murine tracheal epithelial cells. J Virol 81:9469–9480 [CrossRef]
    [Google Scholar]
  97. Noah D. L., Twu K. Y., Krug R. M. 2003; Cellular antiviral responses against influenza A virus are countered at the posttranscriptional level by the viral NS1A protein via its binding to a cellular protein required for the 3′ end processing of cellular pre-mRNAS. Virology 307:386–395 [CrossRef]
    [Google Scholar]
  98. Obenauer J. C., Denson J., Mehta P. K., Su X., Mukatira S., Finkelstein D. B., Xu X., Wang J., Ma J.other authors 2006; Large-scale sequence analysis of avian influenza isolates. Science 311:1576–1580 [CrossRef]
    [Google Scholar]
  99. Opitz B., Rejaibi A., Dauber B., Eckhard J., Vinzing M., Schmeck B., Hippenstiel S., Suttorp N., Wolff T. 2007; IFN β induction by influenza A virus is mediated by RIG-I which is regulated by the viral NS1 protein. Cell Microbiol 9:930–938 [CrossRef]
    [Google Scholar]
  100. Palese P., Shaw M. L. 2007; Orthomyxoviridae : the viruses and their replication. In Fields Virology , 5th edn. pp 1647–1689Edited by Knipe Howley D. M. Philadelphia: Lippincott Williams & Wilkins;
    [Google Scholar]
  101. Park Y. W., Katze M. G. 1995; Translational control by influenza virus. Identification of cis-acting sequences and trans-acting factors which may regulate selective viral mRNA translation. J Biol Chem 270:28433–28439 [CrossRef]
    [Google Scholar]
  102. Petri T., Patterson S., Dimmock N. J. 1982; Polymorphism of the NS1 proteins of type A influenza virus. J Gen Virol 61:217–231 [CrossRef]
    [Google Scholar]
  103. Pichlmair A., Schulz O., Tan C. P., Naslund T. I., Liljestrom P., Weber F., Reis. e Sousa C. 2006; RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates. Science 314:997–1001 [CrossRef]
    [Google Scholar]
  104. Platanias L. C. 2005; Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol 5:375–386 [CrossRef]
    [Google Scholar]
  105. Privalsky M. L., Penhoet E. E. 1981; The structure and synthesis of influenza virus phosphoproteins. J Biol Chem 256:5368–5376
    [Google Scholar]
  106. Qian X. Y., Chien C. Y., Lu Y., Montelione G. T., Krug R. M. 1995; An amino-terminal polypeptide fragment of the influenza virus NS1 protein possesses specific RNA-binding activity and largely helical backbone structure. RNA 1:948–956
    [Google Scholar]
  107. Qiu Y., Krug R. M. 1994; The influenza virus NS1 protein is a poly(A)-binding protein that inhibits nuclear export of mRNAs containing poly(A. J Virol 68:2425–2432
    [Google Scholar]
  108. Qiu Y., Nemeroff M., Krug R. M. 1995; The influenza virus NS1 protein binds to a specific region in human U6 snRNA and inhibits U6–U2 and U6–U4 snRNA interactions during splicing. RNA 1:304–316
    [Google Scholar]
  109. Quinlivan M., Zamarin D., Garcia-Sastre A., Cullinane A., Chambers T., Palese P. 2005; Attenuation of equine influenza viruses through truncations of the NS1 protein. J Virol 79:8431–8439 [CrossRef]
    [Google Scholar]
  110. Randall R. E., Goodbourn S. 2008; Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J Gen Virol 89:1–47 [CrossRef]
    [Google Scholar]
  111. Richt J. A., Lekcharoensuk P., Lager K. M., Vincent A. L., Loiacono C. M., Janke B. H., Wu W. H., Yoon K. J., Webby R. J.other authors 2006; Vaccination of pigs against swine influenza viruses by using an NS1-truncated modified live-virus vaccine. J Virol 80:11009–11018 [CrossRef]
    [Google Scholar]
  112. Russell S. J., Peng K. W. 2007; Viruses as anticancer drugs. Trends Pharmacol Sci 28:326–333 [CrossRef]
    [Google Scholar]
  113. Salvatore M., Basler C. F., Parisien J. P., Horvath C. M., Bourmakina S., Zheng H., Muster T., Palese P., Garcia-Sastre A. 2002; Effects of influenza A virus NS1 protein on protein expression: the NS1 protein enhances translation and is not required for shutoff of host protein synthesis. J Virol 76:1206–1212 [CrossRef]
    [Google Scholar]
  114. Sato Y., Yoshioka K., Suzuki C., Awashima S., Hosaka Y., Yewdell J., Kuroda K. 2003; Localization of influenza virus proteins to nuclear dot 10 structures in influenza virus-infected cells. Virology 310:29–40 [CrossRef]
    [Google Scholar]
  115. Satterly N., Tsai P. L., van Deursen J., Nussenzveig D. R., Wang Y., Faria P. A., Levay A., Levy D. E., Fontoura B. M. 2007; Influenza virus targets the mRNA export machinery and the nuclear pore complex. Proc Natl Acad Sci U S A 104:1853–1858 [CrossRef]
    [Google Scholar]
  116. Schultz-Cherry S., Dybdahl-Sissoko N., Neumann G., Kawaoka Y., Hinshaw V. S. 2001; Influenza virus NS1 protein induces apoptosis in cultured cells. J Virol 75:7875–7881 [CrossRef]
    [Google Scholar]
  117. Seo S. H., Hoffmann E., Webster R. G. 2002; Lethal H5N1 influenza viruses escape host anti-viral cytokine responses. Nat Med 8:950–954 [CrossRef]
    [Google Scholar]
  118. Shimizu K., Iguchi A., Gomyou R., Ono Y. 1999; Influenza virus inhibits cleavage of the HSP70 pre-mRNAs at the polyadenylation site. Virology 254:213–219 [CrossRef]
    [Google Scholar]
  119. Shin Y.-K., Liu Q., Tikoo S. K., Babiuk L. A., Zhou Y. 2007a; Influenza A virus NS1 protein activates the phosphatidylinositol 3-kinase (PI3K)/Akt pathway by direct interaction with the p85 subunit of PI3K. J Gen Virol 88:13–18 [CrossRef]
    [Google Scholar]
  120. Shin Y. K., Li Y., Liu Q., Anderson D. H., Babiuk L. A., Zhou Y. 2007b; SH3 binding motif 1 in influenza A virus NS1 protein is essential for PI3K/Akt signalling pathway activation. J Virol 81:12730–12739 [CrossRef]
    [Google Scholar]
  121. Silverman R. H. 2007; Viral encounters with 2′,5′-oligoadenylate synthetase and RNase L during the interferon antiviral response. J Virol 81:12720–12729 [CrossRef]
    [Google Scholar]
  122. Simonsen L., Clarke M. J., Williamson G. D., Stroup D. F., Arden N. H., Schonberger L. B. 1997; The impact of influenza epidemics on mortality: introducing a severity index. Am J Public Health 87:1944–1950 [CrossRef]
    [Google Scholar]
  123. Solorzano A., Webby R. J., Lager K. M., Janke B. H., Garcia-Sastre A., Richt J. A. 2005; Mutations in the NS1 protein of swine influenza virus impair anti-interferon activity and confer attenuation in pigs. J Virol 79:7535–7543 [CrossRef]
    [Google Scholar]
  124. Stasakova J., Ferko B., Kittel C., Sereinig S., Romanova J., Katinger H., Egorov A. 2005; Influenza A mutant viruses with altered NS1 protein function provoke caspase-1 activation in primary human macrophages, resulting in fast apoptosis and release of high levels of interleukins 1 β and 18. J Gen Virol 86:185–195 [CrossRef]
    [Google Scholar]
  125. Suarez D. L., Perdue M. L. 1998; Multiple alignment comparison of the non-structural genes of influenza A viruses. Virus Res 54:59–69 [CrossRef]
    [Google Scholar]
  126. Subbarao K., Klimov A., Katz J., Regnery H., Lim W., Hall H., Perdue M., Swayne D., Bender C.other authors 1998; Characterization of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory illness. Science 279:393–396 [CrossRef]
    [Google Scholar]
  127. Takizawa T., Ohashi K., Nakanishi Y. 1996; Possible involvement of double-stranded RNA-activated protein kinase in cell death by influenza virus infection. J Virol 70:8128–8132
    [Google Scholar]
  128. Talon J., Horvath C. M., Polley R., Basler C. F., Muster T., Palese P., Garcia-Sastre A. 2000a; Activation of interferon regulatory factor 3 is inhibited by the influenza A virus NS1 protein. J Virol 74:7989–7996 [CrossRef]
    [Google Scholar]
  129. Talon J., Salvatore M., O'Neill R. E., Nakaya Y., Zheng H., Muster T., Garcia-Sastre A., Palese P. 2000b; Influenza A and B viruses expressing altered NS1 proteins: a vaccine approach. Proc Natl Acad Sci U S A 97:4309–4314 [CrossRef]
    [Google Scholar]
  130. Tan S. L., Katze M. G. 1998; Biochemical and genetic evidence for complex formation between the influenza A virus NS1 protein and the interferon-induced PKR protein kinase. J Interferon Cytokine Res 18:757–766 [CrossRef]
    [Google Scholar]
  131. To K. F., Chan P. K., Chan K. F., Lee W. K., Lam W. Y., Wong K. F., Tang N. L., Tsang D. N., Sung R. Y.other authors 2001; Pathology of fatal human infection associated with avian influenza A H5N1 virus. J Med Virol 63:242–246 [CrossRef]
    [Google Scholar]
  132. Treanor J. J., Snyder M. H., London W. T., Murphy B. R. 1989; The B allele of the NS gene of avian influenza viruses, but not the A allele, attenuates a human influenza A virus for squirrel monkeys. Virology 171:1–9 [CrossRef]
    [Google Scholar]
  133. Twu K. Y., Noah D. L., Rao P., Kuo R. L., Krug R. M. 2006; The CPSF30 binding site on the NS1A protein of influenza A virus s a potential antiviral target. J Virol 80:3957–3965 [CrossRef]
    [Google Scholar]
  134. Twu K. Y., Kuo R. L., Marklund J., Krug R. M. 2007; The H5N1 influenza virus NS genes selected after 1998 enhance virus replication in mammalian cells. J Virol 81:8112–8121 [CrossRef]
    [Google Scholar]
  135. Vincent A. L., Ma W., Lager K. M., Janke B. H., Webby R. J., Garcia-Sastre A., Richt J. A. 2007; Efficacy of intranasal administration of a truncated NS1 modified live influenza virus vaccine in swine. Vaccine 25:7999–8009 [CrossRef]
    [Google Scholar]
  136. Wang W., Krug R. M. 1998; U6atac snRNA, the highly divergent counterpart of U6 snRNA, is the specific target that mediates inhibition of AT-AC splicing by the influenza virus NS1 protein. RNA 4:55–64
    [Google Scholar]
  137. Wang W., Riedel K., Lynch P., Chien C. Y., Montelione G. T., Krug R. M. 1999; RNA binding by the novel helical domain of the influenza virus NS1 protein requires its dimer structure and a small number of specific basic amino acids. RNA 5:195–205 [CrossRef]
    [Google Scholar]
  138. Wang X., Li M., Zheng H., Muster T., Palese P., Beg A. A., Garcia-Sastre A. 2000; Influenza A virus NS1 protein prevents activation of NF- κ B and induction of alpha/beta interferon. J Virol 74:11566–11573 [CrossRef]
    [Google Scholar]
  139. Wang X., Basler C. F., Williams B. R., Silverman R. H., Palese P., Garcia-Sastre A. 2002; Functional replacement of the carboxy-terminal two-thirds of the influenza A virus NS1 protein with short heterologous dimerization domains. J Virol 76:12951–12962 [CrossRef]
    [Google Scholar]
  140. Weber F., Wagner V., Rasmussen S. B., Hartmann R., Paludan S. R. 2006; Double-stranded RNA is produced by positive-strand RNA viruses and DNA viruses but not in detectable amounts by negative-strand RNA viruses. J Virol 80:5059–5064 [CrossRef]
    [Google Scholar]
  141. Webster R. G., Bean W. J., Gorman O. T., Chambers T. M., Kawaoka Y. 1992; Evolution and ecology of influenza A viruses. Microbiol Rev 56:152–179
    [Google Scholar]
  142. Wolff T., O'Neill R. E., Palese P. 1996; Interaction cloning of NS1-I, a human protein that binds to the nonstructural NS1 proteins of influenza A and B viruses. J Virol 70:5363–5372
    [Google Scholar]
  143. Wolff T., O'Neill R. E., Palese P. 1998; NS1-Binding protein (NS1-BP): a novel human protein that interacts with the influenza A virus nonstructural NS1 protein is relocalized in the nuclei of infected cells. J Virol 72:7170–7180
    [Google Scholar]
  144. Wolstenholme A. J., Barrett T., Nichol S. T., Mahy B. W. 1980; Influenza virus-specific RNA and protein syntheses in cells infected with temperature-sensitive mutants defective in the genome segment encoding nonstructural proteins. J Virol 35:1–7
    [Google Scholar]
  145. Yin C., Khan J. A., Swapna G. V., Ertekin A., Krug R. M., Tong L., Montelione G. T. 2007; Conserved surface features form the double-stranded RNA binding site of non-structural protein 1 (NS1) from influenza A and B viruses. J Biol Chem 282:20584–20592 [CrossRef]
    [Google Scholar]
  146. Young D. F., Andrejeva L., Livingstone A., Goodbourn S., Lamb R. A., Collins P. L., Elliott R. M., Randall R. E. 2003; Virus replication in engineered human cells that do not respond to interferons. J Virol 77:2174–2181 [CrossRef]
    [Google Scholar]
  147. Zhirnov O. P., Klenk H. D. 2007; Control of apoptosis in influenza virus-infected cells by up-regulation of Akt and p53 signaling. Apoptosis 12:1419–1432 [CrossRef]
    [Google Scholar]
  148. Zhirnov O. P., Konakova T. E., Wolff T., Klenk H. D. 2002; NS1 protein of influenza A virus down-regulates apoptosis. J Virol 76:1617–1625 [CrossRef]
    [Google Scholar]
  149. Zhu Q., Yang H., Chen W., Cao W., Zhong G., Jiao P., Deng G., Yu K., Yang C.other authors 2008; A naturally occurring deletion in its NS gene contributes to the attenuation of an H5N1 swine influenza virus in chickens. J Virol 82:220–228 [CrossRef]
    [Google Scholar]
  150. Zohari S., Gyarmati P., Thoren P., Czifra G., Brojer C., Belak S., Berg M. 2008; Genetic characterization of the NS gene indicates co-circulation of two sub-lineages of highly pathogenic avian influenza virus of H5N1 subtype in Northern Europe in 2006. Virus Genes 36:117–125 [CrossRef]
    [Google Scholar]
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