title: Genomewide analysis of reassortment and evolution of human influenza A(H3N2) viruses circulating between 1968 and 2011.
abstract: Influenza A(H3N2) viruses became widespread in humans during the 1968 H3N2 virus pandemic and have been a major cause of influenza epidemics ever since. These viruses evolve continuously by reassortment and genomic evolution. Antigenic drift is the cause for the need to update influenza vaccines frequently. Using two data sets that span the entire period of circulation of human influenza A(H3N2) viruses, it was shown that influenza A(H3N2) virus evolution can be mapped to 13 antigenic clusters. Here we analyzed the full genomes of 286 influenza A(H3N2) viruses from these two data sets to investigate the genomic evolution and reassortment patterns. Numerous reassortment events were found, scattered over the entire period of virus circulation, but most prominently in viruses circulating between 1991 and 1998. Some of these reassortment events persisted over time, and one of these coincided with an antigenic cluster transition. Furthermore, selection pressures and nucleotide and amino acid substitution rates of all proteins were studied, including those of the recently discovered PB1-N40, PA-X, PA-N155, and PA-N182 proteins. Rates of nucleotide and amino acid substitutions were most pronounced for the hemagglutinin, neuraminidase, and PB1-F2 proteins. Selection pressures were highest in hemagglutinin, neuraminidase, matrix 1, and nonstructural protein 1. This study of genotype in relation to antigenic phenotype throughout the period of circulation of human influenza A(H3N2) viruses leads to a better understanding of the evolution of these viruses.
  
  
  OBJECTIVE
  Each winter, influenza virus infects approximately 5 to 15% of the world's population, resulting in significant morbidity and mortality. Influenza A(H3N2) viruses evolve continuously by reassortment and genomic evolution. This leads to changes in antigenic recognition (antigenic drift) which make it necessary to update vaccines against influenza A(H3N2) viruses frequently. In this study, the relationship of genetic evolution to antigenic change spanning the entire period of A(H3N2) virus circulation was studied for the first time. The results presented in this study contribute to a better understanding of genetic evolution in correlation with antigenic evolution of influenza A(H3N2) viruses.
authors.affiliation: Department of Viroscience, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: Kim B
authors.initials: KB
authors.lastname: Westgeest
authors.forename: Colin A
authors.initials: CA
authors.lastname: Russell
authors.forename: Xudong
authors.initials: X
authors.lastname: Lin
authors.forename: Monique I J
authors.initials: MI
authors.lastname: Spronken
authors.forename: Theo M
authors.initials: TM
authors.lastname: Bestebroer
authors.forename: Justin
authors.initials: J
authors.lastname: Bahl
authors.forename: Ruud
authors.initials: R
authors.lastname: van Beek
authors.forename: Eugene
authors.initials: E
authors.lastname: Skepner
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Halpin
authors.forename: Jan C
authors.initials: JC
authors.lastname: de Jong
authors.forename: Guus F
authors.initials: GF
authors.lastname: Rimmelzwaan
authors.forename: Albert D M E
authors.initials: AD
authors.lastname: Osterhaus
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Smith
authors.forename: David E
authors.initials: DE
authors.lastname: Wentworth
authors.forename: Ron A M
authors.initials: RA
authors.lastname: Fouchier
authors.forename: Miranda
authors.initials: M
authors.lastname: de Graaf
mesh_terms: D019943:Amino Acid Substitution; D003062:Codon; D019143:Evolution, Molecular; D016679:Genome, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000276:immunology; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D053122:Influenza A Virus, H3N2 Subtype / Q000235:genetics* / Q000276:immunology; D007251:Influenza, Human / Q000453:epidemiology* / Q000266:history; D016366:Open Reading Frames; D010802:Phylogeny; D016865:Reassortant Viruses / Q000235:genetics* / Q000276:immunology; D011995:Recombination, Genetic; D012641:Selection, Genetic; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D003062:Codon; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D014764:Viral Proteins