Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Lethal H5N1 influenza viruses escape host anti-viral cytokine responses

An Addendum to this article was published on 05 October 2012

Abstract

The H5N1 influenza viruses transmitted to humans in 1997 were highly virulent, but the mechanism of their virulence in humans is largely unknown. Here we show that lethal H5N1 influenza viruses, unlike other human, avian and swine influenza viruses, are resistant to the antiviral effects of interferons and tumor necrosis factor α. The nonstructural (NS) gene of H5N1 viruses is associated with this resistance. Pigs infected with recombinant human H1N1 influenza virus that carried the H5N1 NS gene experienced significantly greater and more prolonged viremia, fever and weight loss than did pigs infected with wild-type human H1N1 influenza virus. These effects required the presence of glutamic acid at position 92 of the NS1 molecule. These findings may explain the mechanism of the high virulence of H5N1 influenza viruses in humans.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Dose effect and roles of NS1 and HA in H5N1/97 viruses' resistance to cytokines.
Figure 2: Role of the NS gene in the resistance of H5N1 virus to cytokines in vivo.

Similar content being viewed by others

References

  1. De Jong, J.C., Claas, E.C., Osterhaus, A.D., Webster, R.G. & Lim, W.L. A pandemic warning? Nature 389, 554 (1997).

    Article  CAS  Google Scholar 

  2. Claas, E.C.J. et al. Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus. Lancet 351, 472–477 (1998).

    Article  CAS  Google Scholar 

  3. Subbarao, K. et al. Characterization of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory illness. Science 279, 393–396 (1998).

    Article  CAS  Google Scholar 

  4. To, K. et al. Pathology of fatal human infection associated with avian influenza A H5N1 virus. J. Med. Virol. 63, 242–246 (2001).

    Article  CAS  Google Scholar 

  5. Rimmelzwaan, G.F. et al. Pathogenesis of influenza A (H5N1) virus infection in a primate model. J. Virol. 75, 6687–6691 (2001).

    Article  CAS  Google Scholar 

  6. Lu, X. et al. A mouse model for the elevation of pathogenesis and immunity to influenza A (H5N1) viruses isolated from humans. J. Virol. 73, 5903–5911 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Gao, P. et al. Biological heterogeneity, including systemic replication in mice, of H5N1 influenza A virus isolated from humans in Hong Kong. J. Virol. 73, 3184–3189 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Richman, D.D., Murphy, B.R., Baron, S. & Uhlendorf, C. Three strains of influenza A virus (H3N2): Interferon sensitivity in vitro and interferon production in volunteers. J. Clin. Microbiol. 3, 223–226 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Hill, D.A. et al. Evaluation of an interferon inducer in viral respiratory disease. JAMA 219, 1179–1184 (1972).

    Article  CAS  Google Scholar 

  10. Murphy, B.R., Baron, S., Chalhub, E.G., Uhlendorf, C.P. & Chanock, R.M. Temperature-sensitive mutants of influenza virus. IV. Induction of interferon in the nasopharynx by wild-type and a temperature-sensitive recombinant virus. J. Infec. Dis. 128, 488–493 (1973).

    Article  CAS  Google Scholar 

  11. Seo, S.H. & Webster, R.G. Tumor necrosis factor alpha exerts powerful anti-influenza virus effects in lung epithelial cells. J. Virol. 76, 1071–1076 (2002).

    Article  CAS  Google Scholar 

  12. Issacs, A., & Lindenmann, J. Virus interference 1. The interferon. Proc. Roy. Soc. B 147, 258–267.(1957)

    Google Scholar 

  13. Seo, S.H., Goloubeva, O., Webby, R. & Webster, R.G. Characterization of a porcine lung epithelial cell line suitable for influenza virus studies. J. Virol. 75, 9517–9525 (2001).

    Article  CAS  Google Scholar 

  14. Van Reeth, K., Nauwynck, H. & Pensaert, M. Bronchoalveolar interferon-α, tumor necrosis factor-α, interleukin-1, and inflammation during acute influenza in pigs: A possible model for humans? J. Infec. Dis. 177, 1076–1079 (1998).

    Article  CAS  Google Scholar 

  15. Garcia-Sastre, A. et al. Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems. Virology 252, 324–330 (1998).

    Article  CAS  Google Scholar 

  16. Yuan, W. & Krug, R.M. Influenza B virus NS1 protein inhibits conjugation of the interferon (IFN)-induced ubiquitin-like ISG15 protein. EMBO J. 20, 362–371 (2001).

    Article  CAS  Google Scholar 

  17. Hoffmann, E., Neumann, G., Kawaoka, Y., Hobom, G. & Webster, R.G. A DNA transfection system for generation of influenza A virus from eight plasmids. Proc. Natl. Acad. Sci. USA 97, 6108–6113 (2000).

    Article  CAS  Google Scholar 

  18. Hoffmann, E. et al. Characterization of the influenza A virus gene pool in avian species in southern China: Was H6N1 a derivative or a precursor of H5N1? J. Virol. 74, 6309–6315 (2000).

    Article  CAS  Google Scholar 

  19. Guan, Y., Shortridge, K.F., Krauss, S. & Webster, R.G. Molecular characterization of H9N2 influenza viruses: were they the donors of the “internal” genes of H5N1 viruses in Hong Kong? Proc. Natl. Acad. Sci. USA 96, 9363–9567 (1999).

    Article  CAS  Google Scholar 

  20. Lin, Y.P. et al. Avian-to-human transmission of H9N2 subtype influenza A viruses: Relationship between H9N2 and H5N1 human isolates. Proc. Natl. Acad. Sci. USA 97, 9654–9658. (2000).

    Article  CAS  Google Scholar 

  21. Shortridge, K.F. et al. Characterization of avian H5N1 influenza viruses from poultry in Hong Kong. Virology 252, 331–342 (1998).

    Article  CAS  Google Scholar 

  22. Ogawa, T. & Ueda, M. Genes involved in the virulence of an avian influenza virus. Virology 113, 304–313 (1981).

    Article  CAS  Google Scholar 

  23. Bosch, F.X., Orlich, M., Klenk, H.D. & Rott, R. The structure of the hemagglutinin, a determinant for the pathogenicity of influenza viruses. Virology 95, 197–207 (1979).

    Article  CAS  Google Scholar 

  24. Hatta, M., Gao, P., Halfmann, P. & Kawaoka, Y. Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science 293, 1840–1842 (2001).

    Article  CAS  Google Scholar 

  25. Taubenberger, J.K., Reid, A.H., Krafft, A.E., Bijwaard, K.E. & Fanning, T.G. Initial genetic characterization of the 1918 “Spanish” influenza virus. Science 275, 1793–1796 (1997).

    Article  CAS  Google Scholar 

  26. Qian, X.Y. et al. 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 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Ennis, F.A. et al. Interferon induction and increased natural killer-cell activity in influenza infections in man. Lancet 2, 891–893 (1981).

    Article  CAS  Google Scholar 

  28. Green, J.A., Charette, R.P., Yeh, T.-J. & Smith, C.B. Presence of interferon in acute- and convalescent-phase sera of humans with influenza or an influenza-like illness of undetermined etiology. J. Infect. Dis. 145, 837–841 (1982).

    Article  CAS  Google Scholar 

  29. Fritz, R.S. et al. Nasal cytokine and chemokine responses in experimental influenza A virus infection: Results of a placebo-controlled trial of intravenous zanamivir treatment. J. Infect. Dis. 180, 586 (1999).

  30. Lu, Y, Wambach, M., Katze, M.G. & Krug, R.M. 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 (1995).

  31. Talon, J. et al. Activation of interferon regulatory factor 3 is inhibited by the influenza A virus NS1 protein. J. Virol. 74, 7989 (2000).

    Article  CAS  Google Scholar 

  32. Naniche, D. et al. Evasion of host defenses by measles virus: Wild-type measles virus infection interferes with induction of α/β interferon production. J. Virol. 74, 7478 (2000).

    Article  CAS  Google Scholar 

  33. Basler, C.F. et al. 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. USA 98, 2746–2751 (2001).

    Article  CAS  Google Scholar 

  34. Zitzow, L.A. et al. Pathogenesis of avian influenza A (H5N1) viruses in ferrets. J. Virol. 76, 4420–4429 (2002).

    Article  CAS  Google Scholar 

  35. Jameson J., Cruz J., Terajima, M. & Ennis, F.A. Human CD8+ and CD4+ T lymphocyte memory to influenza A viruses of swine and avian species. J. Immunol. 162, 7578–7583 (1999).

    CAS  PubMed  Google Scholar 

  36. Staeheli, P. et al. Influenza virus-susceptible mice carry Mx genes with a large deletion or a nonsense mutation. Mol. Cell Biol. 8, 4518–4523 (1988).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Peiris, Y. Guan and K. Shortridge for providing the H5N1 influenza viruses; S. Krauss, D. Walker, J. Humberd, P. Seiler and R. Menon for technical support; L. Twit for manuscript preparation; and S. Naron for editorial assistance. This work was supported by Public Health Service grants AI-29860, AI-95357 and CA-21765, and by the American Lebanese Syrian Associated Charities (ALSAC).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Robert G. Webster.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Heui Seo, S., Hoffmann, E. & Webster, R. Lethal H5N1 influenza viruses escape host anti-viral cytokine responses. Nat Med 8, 950–954 (2002). https://doi.org/10.1038/nm757

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm757

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing