Sequence of the 1918 pandemic influenza virus nonstructural gene (NS) segment and characterization of recombinant viruses hearing the 1918 NS genes

The influenza A virus pandemic of 1918-1919 resulted in an estimated 20-40 million deaths worldwide. The hemagglutinin and neuraminidase sequences of the 1918 virus were previously determined, We here report the sequence of t he A/Brevig Mission/1/18 (H1N1) virus nonstructural (NS) segment encoding t wo proteins, NS1 and nuclear export protein. Phylogenetically, these genes appear to be close to the common ancestor of subsequent human and classical swine strain NS genes. Recently, the influenza A virus NS1 protein was sho wn to be a type I IFN antagonist that plays an important role in viral path ogenesis. By using the recently developed technique of generating influenza A viruses entirely from cloned cDNAs, the hypothesis that the 1918 virus N S1 gene played a role in virulence was tested in a mouse model, In a BSL3laboratory, viruses were generated that possessed either the 1918 NS1 gene alone or the entire 1918 NS segment in a background of influenza A/WSN/33 ( H1N1), a mouse-adapted virus derived from a human influenza strain first is olated in 1933, These 1918 NS viruses replicated well in tissue culture but were attenuated in mice as compared with the isogenic control viruses. Thi s attenuation in mice may be related to the human origin of the 1918 NS1 ge ne, These results suggest that interaction of the NS1 protein with host-cel l factors plays a significant role in viral pathogenesis.