Recombinant influenza virus with a pandemic H2N2 polymerase complex has a higher adaptive potential than one with seasonal H2N2 polymerase complex

Abstract

The reassortment of influenza viral gene segments plays a key role in the genesis of pandemic strains. All of the last three pandemic viruses contained reassorted polymerase complexes with subunits derived from animal viruses, suggesting that the acquisition of a reassorted polymerase complex might have a role in generating these pandemic viruses. Here, we studied polymerase activities of the pandemic H2N2, seasonal H2N2 and pandemic H3N2 viruses. We observed that the viral ribonucleoprotein (vRNP) of pandemic H2N2 virus has a highly robust activity. The polymerase activity of seasonal H2N2 viruses, however, was much reduced. We further identified three mutations (PB2-I114V, PB1-S261N and PA-D383N) responsible for the reduced activity. To determine the potential impact of viral polymerase activity on the viral life cycle, recombinant H3N2 viruses carrying pandemic and seasonal H2N2 vRNP were studied in cell cultures supplemented with oseltamivir carboxylate and tested for their abilities to develop adaptive or resistant mutations. It was found that the recombinant virus with pandemic H2N2 vRNP was more capable of restoring the viral fitness than the one with seasonal vRNP. These results suggest that a robust vRNP is advantageous to influenza virus to cope with a new selection pressure.