Whole-Genome Analysis of Human Influenza A Virus Reveals Multiple Persistent Lineages and Reassortment among Recent H3N2 Viruses

Abstract

Understanding the evolution of influenza A viruses in humans is important for surveillance and vaccine strain selection. We performed a phylogenetic analysis of 156 complete genomes of human H3N2 influenza A viruses collected between 1999 and 2004 from New York State, United States, and observed multiple co-circulating clades with different population frequencies. Strikingly, phylogenies inferred for individual gene segments revealed that multiple reassortment events had occurred among these clades, such that one clade of H3N2 viruses present at least since 2000 had provided the hemagglutinin gene for all those H3N2 viruses sampled after the 2002–2003 influenza season. This reassortment event was the likely progenitor of the antigenically variant influenza strains that caused the A/Fujian/411/2002-like epidemic of the 2003–2004 influenza season. However, despite sharing the same hemagglutinin, these phylogenetically distinct lineages of viruses continue to co-circulate in the same population. These data, derived from the first large-scale analysis of H3N2 viruses, convincingly demonstrate that multiple lineages can co-circulate, persist, and reassort in epidemiologically significant ways, and underscore the importance of genomic analyses for future influenza surveillance.

Shaping the phylogenetic tree of influenza by cross-immunity

“…Recent studies of the population genetics of influenza based on the whole genome show that influenza is considerably more polymorphic than previously thought in particular in its internal structures and that reassortment may generate at least some of the novel viral variants (Holmes et al, 2005). These findings question our interpretation of the relatedness among strains as solely characterized by amino-acid differences in the HA-gene but not the relatednesses themselves as they may be seen as a schematic representation of the observed cross-reactivity.…”

“…Specific strains appear to be well suited for the low-transmission period (Gog et al, 2003) and in addition genetic and antigenic variation is always present at least at the global and regional scales (Plotkin et al, 2002;Holmes et al, 2005). Still within a single epidemic, variation appears to be 6 limited (Schweiger et al, 2002;Shih et al, 2005).…”

Influenza A virus nucleoprotein selectively decreases neuraminidase gene-segment packaging while enhancing viral fitness and transmissibility

“…Genome segmentation complements the high mutation rate of IAV by facilitating reassortment, which can maximize positive intergenic epistasis (2)(3)(4)(5) and allow selective elimination of segments with deleterious mutations (6,7). Although reassortment is the most obvious and best-characterized benefit of segmentation, there are likely additional evolutionary advantages.…”

Critical role of segment-specific packaging signals in genetic reassortment of influenza A viruses

“…The fragmented nature of the genome allows the exchange of gene segments when two or more influenza viruses coinfect the same cell, in a process named "genetic reassortment" (4). Genetic reassortment is a major feature of influenza evolution and cross-species transmission and also is important for the generation of antigenically novel isolates by introducing novel HA segments in compatible genetic backgrounds (5)(6)(7). Future pandemic viruses most likely will carry different HA genes to which human populations are immunologically naive.…”