Comparative Dynamics and Distribution of Influenza Drug Resistance Acquisition to Protein M2 and Neuraminidase Inhibitors

Although efficient influenza vaccines are designed on a regular basis, the only protection of human populations against an unforeseen virus such as during the H1N1 pandemic in 2009 might be antiviral drugs. Adamantanes and neuraminidase inhibitors (Oseltamivir) represent two classes of such drugs that target the viral matrix protein 2 and neuraminidase, respectively. Although the emergence of resistance to both drugs has been described, the timing and spread of the acquisition of either single or dual resistances by different hosts is still unclear. Using a multilayered phylogenetic approach based on relaxed molecular clocks and large-scale maximum likelihood approaches, we show that Adamantane resistance evolved multiple times in various subtypes and hosts, possibly in breeding contexts (swine); and Oseltamivir resistance was also found in different subtypes and hosts, but its transmission is only sustained in humans. Furthermore, the dynamics of the emergence of antiviral resistance were examined for each drug. This showed that although the first mutations conferring resistance to Adamantanes precede US Food and Drug Administration (FDA) approval, general resistance emerged 15–38 years post-drug approval. This is in contrast to Oseltamivir resistance mutations that emerged at most 7 years after FDA approval of the drug. This study demonstrates the power of large-scale analyses to uncover and monitor the emergence dynamics of drug resistance.