Changing selective pressure during antigenic changes in human influenza H3

PLoS Pathog. 2008 May 2;4(5):e1000058. doi: 10.1371/journal.ppat.1000058.


The rapid evolution of influenza viruses presents difficulties in maintaining the optimal efficiency of vaccines. Amino acid substitutions result in antigenic drift, a process whereby antisera raised in response to one virus have reduced effectiveness against future viruses. Interestingly, while amino acid substitutions occur at a relatively constant rate, the antigenic properties of H3 move in a discontinuous, step-wise manner. It is not clear why this punctuated evolution occurs, whether this represents simply the fact that some substitutions affect these properties more than others, or if this is indicative of a changing relationship between the virus and the host. In addition, the role of changing glycosylation of the haemagglutinin in these shifts in antigenic properties is unknown. We analysed the antigenic drift of HA1 from human influenza H3 using a model of sequence change that allows for variation in selective pressure at different locations in the sequence, as well as at different parts of the phylogenetic tree. We detect significant changes in selective pressure that occur preferentially during major changes in antigenic properties. Despite the large increase in glycosylation during the past 40 years, changes in glycosylation did not correlate either with changes in antigenic properties or with significantly more rapid changes in selective pressure. The locations that undergo changes in selective pressure are largely in places undergoing adaptive evolution, in antigenic locations, and in locations or near locations undergoing substitutions that characterise the change in antigenicity of the virus. Our results suggest that the relationship of the virus to the host changes with time, with the shifts in antigenic properties representing changes in this relationship. This suggests that the virus and host immune system are evolving different methods to counter each other. While we are able to characterise the rapid increase in glycosylation of the haemagglutinin during time in human influenza H3, an increase not present in influenza in birds, this increase seems unrelated to the observed changes in antigenic properties.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigenic Variation / genetics*
  • Antigenic Variation / immunology
  • Antigens, Viral / immunology
  • COS Cells
  • Cell Fusion
  • Chlorocebus aethiops
  • DNA, Viral / genetics
  • Evolution, Molecular*
  • Genetic Drift*
  • HeLa Cells
  • Hemagglutinin Glycoproteins, Influenza Virus / genetics
  • Hemagglutinin Glycoproteins, Influenza Virus / immunology
  • Humans
  • Influenza A virus / genetics*
  • Influenza A virus / immunology
  • Influenza A virus / pathogenicity
  • Influenza, Human / genetics
  • Influenza, Human / immunology
  • Influenza, Human / virology*
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / virology
  • Macrophages / immunology
  • Macrophages / virology
  • Selection, Genetic*


  • Antigens, Viral
  • DNA, Viral
  • Hemagglutinin Glycoproteins, Influenza Virus