Characterization of the 1918 influenza virus polymerase genes

Nature. 2005 Oct 6;437(7060):889-93. doi: 10.1038/nature04230.


The influenza A viral heterotrimeric polymerase complex (PA, PB1, PB2) is known to be involved in many aspects of viral replication and to interact with host factors, thereby having a role in host specificity. The polymerase protein sequences from the 1918 human influenza virus differ from avian consensus sequences at only a small number of amino acids, consistent with the hypothesis that they were derived from an avian source shortly before the pandemic. However, when compared to avian sequences, the nucleotide sequences of the 1918 polymerase genes have more synonymous differences than expected, suggesting evolutionary distance from known avian strains. Here we present sequence and phylogenetic analyses of the complete genome of the 1918 influenza virus, and propose that the 1918 virus was not a reassortant virus (like those of the 1957 and 1968 pandemics), but more likely an entirely avian-like virus that adapted to humans. These data support prior phylogenetic studies suggesting that the 1918 virus was derived from an avian source. A total of ten amino acid changes in the polymerase proteins consistently differentiate the 1918 and subsequent human influenza virus sequences from avian virus sequences. Notably, a number of the same changes have been found in recently circulating, highly pathogenic H5N1 viruses that have caused illness and death in humans and are feared to be the precursors of a new influenza pandemic. The sequence changes identified here may be important in the adaptation of influenza viruses to humans.

Publication types

  • Historical Article
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptation, Physiological / genetics
  • Amino Acid Substitution / genetics
  • Animals
  • Birds / virology
  • Evolution, Molecular*
  • Genes, Viral / genetics*
  • Genome, Viral
  • History, 20th Century
  • Humans
  • Influenza A virus / enzymology*
  • Influenza A virus / genetics*
  • Influenza A virus / pathogenicity
  • Influenza, Human / epidemiology
  • Influenza, Human / history*
  • Influenza, Human / virology*
  • Mutation / genetics
  • Phylogeny
  • RNA-Dependent RNA Polymerase / chemistry
  • RNA-Dependent RNA Polymerase / genetics*
  • Reassortant Viruses / genetics
  • Time Factors
  • Viral Proteins / chemistry
  • Viral Proteins / genetics
  • Virus Replication / genetics


  • PA protein, influenza viruses
  • PB2 protein, influenza virus
  • Viral Proteins
  • influenza virus polymerase basic protein 1
  • RNA-Dependent RNA Polymerase