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.

Positive selection for gains of N-linked glycosylation sites in hemagglutinin during evolution of H3N2 human influenza A virus

“…It has been proposed that the gain and loss of N-linked glycosylation sites may not have been involved in antigenic changes of HA in human H3N2 virus, because the gain and loss were not found to be coincided with the transition of antigenic clusters (Smith et al, 2004), as well as the increase in the rate of change in the substitution pattern at amino acid sites (Blackburne et al, 2008). However, the existence of antigenic clusters in human H3N2 virus itself has been questioned (Shih et al, 2007;Suzuki, 2008b;Bhatt et al, 2011).…”

“…In the ectodomain, asparagine [N] of the sequon, which is defined as the sequence of N, any amino acid except for proline [P], and serine [S] or threoEdited by Fumio Tajima * Corresponding author. E-mail: yossuzuk@nsc.nagoya-cu.ac.jp nine [T], mostly serves as an N-linked glycosylation site, where high-mannose or complex oligosaccharide is attached with various forms (Hebert et al, 1997;Schulze, 1997;Daniels et al, 2003;Abe et al, 2004;Blackburne et al, 2008;Das et al, 2010). O-linked glycosylation has not been reported for influenza A virus.…”

Evidence for N-Glycan Shielding of Antigenic Sites during Evolution of Human Influenza A Virus Hemagglutinin

“…It was speculated that the addition of NGS to the globular head region conferred selective advantages to the viruses by preventing the binding of Ab to AS. However, this hypothesis has been questioned, because the gain of NGS in the globular head region of HA did not appear to influence the amino acid variation at AS, and no correlation was observed between the transitions of antigenic clusters and gains or losses of NGS during the evolution of human A/H3N2 virus (4,8).…”

Emergency surveillance of influenza during 2009 in the Chinese city of Qingdao

“…Six amino acid mutations (E62K, N144K, K158N, K173Q, N189K and V213A) in the HA protein of the H3N2 influenza viruses were defined when compared with those isolated in 2007–2008. All these mutations were located in antigenic sites under positive selection 7 , 8 …”