Evolutionary analysis of human H2N2 and early H3N2 influenza viruses: evidence for genetic divergence and multiple reassortment among H2N2 and/or H3N2 viruses

Abstract

Pandemic influenza H2N2 viruses emerged in humans in 1957 and caused widespread morbidity and mortality in humans until 1968 when they were displaced by emerging H3N2 viruses. Although it is known that both the appearance and disappearance of H2N2 viruses involved reassortment between human and avian influenza viruses, genetic characterization of these viruses is limited. In this study, detailed genetic analysis of all eight gene segments of human H2N2 viruses isolated from 1957 until 1968 from geographically diverse regions was undertaken to establish a better understanding of the evolutionary nature of this virus. In addition, a number of human H3N2 viruses isolated from 1968 until 1972 were examined to investigate genetic events associated with the emergence of pandemic H3N2 viruses in humans. Phylogenic analysis of all gene segments of human H2N2 viruses consistently demonstrated divergent evolution. Genes of late H2N2 isolates were located in either of two distinct clades (I and II). Analysis of H3N2 viruses of 1968 revealed that all gene segments that were retained from H2N2 viruses were most similar to H2N2 virus genes of clade I. However, genes of both lineages were found to cocirculate among H3N2 isolates of 1969–1971. Furthermore, each gene segment demonstrated unique phylogenic topologies, indicating multiple reassortment events between late H2N2 and/or H3N2 viruses. The H3N2 viruses of 1972 analyzed here appeared to possess the genome constellation that represents the ancestral virus of contemporary H3N2 viruses. This constellation was first observed among isolates of 1970 and was distinct from that found among the earliest human H3N2 viruses from 1968. This evidence demonstrates that establishment of H3N2 viruses in humans was associated with multiple-reassortment events that contributed to genetic diversity among viruses.