Emergence and Fixing of Antiviral Resistance in Influenza A Via Recombination and Hitch Hiking

The dramatic rise of oseltamivir resistance in the H1N1 serotype in the 2007/2008 season and the fixing of H274Y in the 2008/2009 season has raised concerns regarding individuals at risk for seasonal influenza, as well as development of similar resistance in the H5N1 serotype. Previously, oseltamivir resistance produced changes in H1N1 and H3N2 at multiple positions in treated patients. In contrast, the recently reported resistance involved patients who had not recently taken oseltamivir. Moreover, the resistance was limited to the H1N1 which had acquired H274Y. Using phylogenetic analysis I show that the fixing of H274Y was due to hitch hiking on a genetic background that acquired key changes from another circulating sub-clade. H274Y jumped from clade 2C (Hong Kong/2562/2006-like) to clade 1 (New Caledonia/20/1999-like) to clade 2B (Brisbane/59/2007-like) which included multiple introductions. Sub-clades that had acquired key changes on the neuramindase and hemagglutinin genes expanded and fixed of H274Y on H1N1. These changes led to the spread of adamantane resistance on clade 2C outside of Asia, followed by the spread of oseltamivir resistance in 2007/2008 and the fixing of H274Y in 2008/2009. The hemagglutinin change, A193T, was a key component and the coincident polymorphism, S193F, was linked to the fixing of adamantane resistance in H3N2. The aggregation of key polymorphisms onto different genetic backgrounds supports a mechanism of homologous recombination between co-circulating influenza sub-clades, and provides a rationale for the prediction of vaccine targets and emergence of antiviral resistance