Lethal H5N1 influenza viruses escape host anti-viral cytokine responses

Nat Med. 2002 Sep;8(9):950-4. doi: 10.1038/nm757. Epub 2002 Aug 26.


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 alpha. 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Cytokines / immunology*
  • Drug Resistance, Multiple, Viral / genetics
  • Drug Resistance, Multiple, Viral / immunology*
  • Epithelial Cells / drug effects
  • Epithelial Cells / virology
  • Humans
  • Influenza A Virus, H5N1 Subtype*
  • Influenza A virus / drug effects
  • Influenza A virus / genetics
  • Influenza A virus / pathogenicity*
  • Influenza, Human / immunology*
  • Influenza, Human / transmission
  • Influenza, Human / virology*
  • Interferon-alpha / immunology
  • Interferon-alpha / pharmacology
  • Interferon-gamma / immunology
  • Interferon-gamma / pharmacology
  • Point Mutation
  • Swine
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / pharmacology
  • Viral Nonstructural Proteins / drug effects
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / metabolism*
  • Virulence / genetics


  • Cytokines
  • INS1 protein, influenza virus
  • Interferon-alpha
  • Tumor Necrosis Factor-alpha
  • Viral Nonstructural Proteins
  • Interferon-gamma