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

Edward C Holmes,Elodie Ghedin,Kirsten St George,Bryan T Grenfell,Jill Taylor,Steven L Salzberg,David J Lipman,Claire M Fraser,Jeffery K Taubenberger,Yiming Bao,Naomi Miller

doi:10.1371/journal.pbio.0030300

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.

Highlights

Influenza A viruses are negative-strand RNA viruses of the Family Orthomyxoviridae that infect a wide variety of warmblooded animals, including domestic and wild birds and mammals
Three major clusters of sequences were apparent in phylogenetic trees of the 156 complete genomes of H3N2 influenza A viruses sampled from New York State
These corresponded to particular influenza seasons: (a) 1999–2000, (b) 2001–2002 and 2002–2003 together, and (c) 2003–2004 (Figure 1)

Summary

Introduction

Influenza A viruses are negative-strand RNA viruses of the Family Orthomyxoviridae that infect a wide variety of warmblooded animals, including domestic and wild birds and mammals (e.g., humans, pigs, and horses). The natural reservoir for influenza virus is thought to be wild waterfowl, and genetic material from avian strains episodically emerges in strains infectious to humans. These human viruses continually circulate in yearly epidemics (mainly during the winter months in temperate climates), and antigenically novel strains emerge sporadically as pandemic viruses [1,2]. Influenza epidemics boost the annual mortality level above this average, causing 10,000–15,000 additional deaths. And unpredictably, global pandemics of influenza occur, infecting 20% to 40% of the population in a single year and raising death rates dramatically above normal levels. How and when novel influenza viruses emerge as pandemic strains and their precise mechanisms of pathogenesis are still not understood

Methods

Results

Conclusion