The virulence of the 1918 pandemic influenza virus: unraveling the enigma.

The 1918 influenza pandemic caused acute illness in 25-30% of the world's population and resulted in the death of up to 40 million people. Using lung tissue of 1918 influenza victims, the complete genomic sequence of the 1918 influenza virus is being deduced. Neither the 1918 hemagglutinin nor neuraminidase genes possess mutations known to increase tissue tropicity that account for virulence of other influenza virus strains, such as A/WSN/33 or the highly pathogenic avian influenza H5 or H7 viruses. Using reverse genetics approaches, influenza virus constructs containing the 1918 hemagglutinin and neuraminidase on an A/WSN/33 virus background were lethal in mice. The genotypic basis of this virulence has not yet been elucidated. The complete sequence of the non-structural (NS) gene segment of the 1918 virus was deduced and also tested to determine the validity of the hypothesis that enhanced virulence in 1918 could have been due to type I interferon inhibition by the NS1 protein. Results from these experiments suggest that in human cells the 1918 NS1 is a very effective interferon antagonist. Sequence analysis of the 1918 influenza virus is allowing us to test hypotheses as to the origin and virulence of this strain. This information should help elucidate how pandemic influenza virus strains emerge and what genetic features contribute to virulence in humans.