TY - JOUR T1 - Geometric constraints dominate the antigenic evolution of influenza H3N2 hemagglutinin JF - bioRxiv DO - 10.1101/014183 SP - 014183 AU - Austin G. Meyer AU - Claus O. Wilke Y1 - 2015/01/01 UR - http://biorxiv.org/content/early/2015/02/28/014183.1.abstract N2 - We have carried out a comprehensive analysis of the determinants of human influenza A H3 hemagglutinin evolution, considering three distinct predictors of evolutionary variation at individual sites: solvent accessibility (as a proxy for protein fold stability and/or conservation), experimental epitope sites (as a proxy for host immune bias), and proximity to the receptor-binding region (as a proxy for protein function). We have found that these three predictors individually explain approximately 15% of the variation in site-wise dN/dS. However, the solvent accessibility and proximity predictors seem largely independent of each other, while the epitope sites are not. In combination, solvent accessibility and proximity explain 32% of the variation in dN/dS. Incorporating experimental epitope sites into the model adds only an additional 2 percentage points. We have also found that the historical H3 epitope sites, which date back to the 1980s and 1990s, show only weak overlap with the latest experimental epitope data, and we have defined a novel set of four epitope groups which are experimentally supported and cluster in 3D space. Finally, sites with dN/dS > 1, i.e., the sites most likely driving seasonal immune escape, are not correctly predicted by either historical or experimental epitope sites, but only by proximity to the receptor-binding region. In summary, proximity to the receptor-binding region, rather than host immune bias, seems to be the primary determinant of H3 immune-escape evolution.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 immune response of people previously infected. Which sites in the virus’ genome allow this immune escape is not entirely understood, but conventional wisdom states that specific “immune epitope sites” in the protein hemagglutinin are primarily responsible, and these sites are commonly targeted by vaccine development efforts. Here, we survey all available experimental data on immune epitopes in hemagglutinin, and we demonstrate that these immune epitope sites may not be that crucial for influenza evolution. Instead, we propose and find evidence for a simple geometrical model: sites that are closest to the location where the virus binds the human receptor (i.e, the furthest away from the viral surface) are the primary driver of immune escape. ER -