Geometric Constraints Dominate the Antigenic Evolution of Influenza H3N2 Hemagglutinin

Austin G. Meyer, Claus O. Wilke, Jesse D Bloom
2015 PLoS Pathogens  
We have carried out a comprehensive analysis of the determinants of human influenza A H3 hemagglutinin evolution. We consider three distinct predictors of evolutionary variation at individual sites: solvent accessibility (as a proxy for protein fold stability and/or conservation), Immune Epitope Database (IEDB) epitope sites (as a proxy for host immune bias), and proximity to the receptor-binding region (as a proxy for one of the functions of hemagglutinin-to bind sialic acid). Individually,
more » ... se quantities explain approximately 15% of the variation in site-wise dN/dS. In combination, solvent accessibility and proximity explain 32% of the variation in dN/dS; incorporating IEDB epitope sites into the model adds only an additional 2 percentage points. Thus, while solvent accessibility and proximity perform largely as independent predictors of evolutionary variation, they each overlap with the epitope-sites predictor. Furthermore, we find that the historical H3 epitope sites, which date back to the 1980s and 1990s, only partially overlap with the experimental sites from the IEDB, and display similar overlap in predictive power when combined with solvent accessibility and proximity. We also find that sites with dN/dS > 1, i.e., the sites most likely driving seasonal immune escape, are not correctly predicted by either historical or IEDB epitope sites, but only by proximity to the receptor-binding region. In summary, a simple geometric model of HA evolution outperforms a model based on epitope sites. These results suggest that either the available epitope sites do not accurately represent the true influenza antigenic sites or that host immune bias may be less important for influenza evolution than commonly thought. Author Summary The influenza virus is one of the most rapidly evolving human viruses. Every year, it accumulates mutations that allow it to evade the host immune response of previously infected individuals. Which sites in the virus' genome allow this immune escape and the manner of escape is not entirely understood, but conventional wisdom states that specific "immune PLOS Pathogens |
doi:10.1371/journal.ppat.1004940 pmid:26020774 pmcid:PMC4447415 fatcat:jypghngagneilfgt7qngxnmlu4