Changing Selective Pressure during Antigenic Changes in Human Influenza H3

Abstract

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. H3N2-type influenza is responsible for widespread disease and significant mortality. The virus evolves rapidly, changing its antigenic properties, allowing it to escape clearance by the immune response as well as complicating the maintenance of vaccine effectiveness. Part of this evolution has been the rapid increase in glycosylation, an increase not observed either in H9 evolution in birds or in H1 evolution in humans. It has been observed that the antigenic properties change in a punctuated, discontinuous manner. This could be either because some mutations are more significant than others, or it could mean that the antigenic changes correspond to adjustments in the antagonistic relationship between virus and host. By studying the sequence evolution of the H3 haemagglutinin, we can demonstrate that the selective pressure acting on the virus protein changes with time, and that these changes are especially rapid during changes in antigenic properties. This indicates that the antigenic changes correspond to modifications in the virus–host relationship. Surprisingly, neither the changes in selective pressure nor the changes in antigenic properties correspond to changes in glycosylation.