The mechanism of resistance to favipiravir in influenza.
te Velthuis, Arend
Fletcher, Robert A
Proceedings of the National Academy of Sciences of the United States of America
National Academy of Sciences
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Goldhill, D. H., te Velthuis, A., Fletcher, R. A., Langat, P., Zambon, M., Lackenby, A., & Barclay, W. S. (2018). The mechanism of resistance to favipiravir in influenza.. Proceedings of the National Academy of Sciences of the United States of America, 115 (45), 11613-11618. https://doi.org/10.1073/pnas.1811345115
Favipiravir is a broad-spectrum antiviral that has shown promise in treatment of influenza virus infections. While emergence of resistance has been observed for many anti-influenza drugs, to date, clinical trials and laboratory studies of favipiravir have not yielded resistant viruses. Here we show evolution of resistance to favipiravir in the pandemic H1N1 influenza A virus in a laboratory setting. We found that two mutations were required for robust resistance to favipiravir. We demonstrate that a K229R mutation in motif F of the PB1 subunit of the influenza virus RNA-dependent RNA polymerase (RdRP) confers resistance to favipiravir in vitro and in cell culture. This mutation has a cost to viral fitness, but fitness can be restored by a P653L mutation in the PA subunit of the polymerase. K229R also conferred favipiravir resistance to RNA polymerases of other influenza A virus strains and its location within a highly conserved structural feature of the RdRP suggests that other RNA viruses might also acquire resistance through mutations in motif F. The mutations identified here could be used to screen influenza virus infected patients treated with favipiravir for the emergence of resistance.
Animals, Dogs, Amides, Pyrazines, RNA Replicase, Arginine, Lysine, Protein Subunits, Viral Proteins, Antiviral Agents, Microbial Sensitivity Tests, Drug Resistance, Viral, Virus Replication, Gene Expression, Mutation, Influenza A Virus, H1N1 Subtype, Madin Darby Canine Kidney Cells
Wellcome Trust (206579/Z/17/Z)
Isaac Newton Trust (17.37 (r))
External DOI: https://doi.org/10.1073/pnas.1811345115
This record's URL: https://www.repository.cam.ac.uk/handle/1810/286306
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/