Rapid rise of antiviral resistance in influenza not caused by drug selection pressure

In many areas of the world, the predominant strain of human influenza virus (A/H3N2) has become rapidly resistant to a major class of antiviral drugs: adamantanes. In the US, China and Japan, more than 90% viruses circulating in the 2005-2006 'flu season were resistant, compared with fewer than 5% before 2003.

In almost all cases, adamantane resistance arises from a single amino acid change in a membrane protein. The question is, does resistance arise in response to selection by antiviral drugs, or because it is "piggybacking" advantageous mutations elsewhere in the influenza genome? The answer is important, because it affects the practicability of attempting to combat resistance by limiting use of the drugs.

A new phylogenetic analysis by an international team of researchers, including Eddie Holmes and Bryan Grenfell, favors the "piggybacking" hypothesis. The team examined the genomes of viruses isolated from New Zealand, Australia, Japan and the US between 2004 and 2006. All adamantane-resistant viruses examined belonged to a distinct lineage (the N-lineage) that first circulated in the Southern Hemisphere and Asia in 2005, then spread to the northern hemisphere during 2006. This N-lineage appears to have arisen from reassortment between two other influenza A/H3N2 lineages.

In a paper in Molecular Biology and Evolution, the researchers discuss how their findings suggest that the spread of adamantane resistance is unlikely to be due to selection by the drug; rather, it appears to have arisen as a result of interactions with mutations elsewhere in the genome. This suggests that lowering adamantane use may have no effect on the spread of the resistant viruses. Further, it shows that selection by drugs may not be the only factor affecting the evolution and spread of drug resistance in human pathogens.

Written By: Lone Simonsen, Cн©cile Viboud, Bryan T. Grenfell, Jonathan Dushoff, Lance Jennings, Marita Smit, Catherine Macken, Mami Hata, Julia Gog, Mark A Miller, & Edward C. Holmes

Paper Url:

Paper Id: 10.1093/molbev/msm103