Recent Human Influenza A/H3N2 Virus Evolution Driven by Novel Selection Factors in Addition to Antigenic Drift

Background. Examination of the evolutionary dynamics of complete influenza viral genomes reveals that other processes, in conjunction with antigenic drift, play important roles in viral evolution and selection, but there is little biological evidence to support these genomic data. Previous work demonstrated that after the A/Fujian/411/2002-like H3N2 influenza A epidemic during 2003-2004, a preexisting nondominant Fujian-like viral clade gained a small number of changes in genes encoding the viral polymerase complex, along with several changes in the antigenic regions of hemagglutinin, and in a genome-wide selective sweep, it replaced other co-circulating H3N2 clades. Methods. Representative strains of these virus clades were evaluated in vitro and in vivo. Results. The newly dominant 2004-2005 A/California/7/2004-like H3N2 clade, which featured 2 key amino acid changes in the polymerase PA segment, grew to higher titers in MDCK cells and ferret tissues and caused more-severe disease in ferrets. The polymerase complex of this virus demonstrated enhanced activity in vitro, correlating directly to the enhanced replicative fitness and virulence in vivo. Conclusion. These data suggest that influenza strains can be selected in humans through mutations that increase replicative fitness and virulence, in addition to the well-characterized antigenic changes in the surface glycoproteins.