Department of Medicine; Department of Microbiology and Physiological Systems; Program in Bioinformatics and Integrative Biology; Department of Biochemistry and Molecular Pharmacology
Genetics and Genomics | Immunoprophylaxis and Therapy | Influenza Virus Vaccines | Population Biology
Influenza virus inflicts a heavy death toll annually and resistance to existing antiviral drugs has generated interest in the development of agents with novel mechanisms of action. Favipiravir is an antiviral drug that acts by increasing the genome-wide mutation rate of influenza A virus (IAV). Potential synergistic benefits of combining oseltamivir and favipiravir have been demonstrated in animal models of influenza, but the population-level effects of combining the drugs are unknown. In order to elucidate the underlying evolutionary processes at play, we performed genome-wide sequencing of IAV experimental populations subjected to serial passaging in vitro under a combined protocol of oseltamivir and favipiravir. We describe the interplay between mutation, selection, and genetic drift that ultimately culminates in population extinction. In particular, selective sweeps around oseltamivir resistance mutations reduce genome-wide variation while deleterious mutations hitchhike to fixation given the increased mutational load generated by favipiravir. This latter effect reduces viral fitness and accelerates extinction compared with IAV populations treated with favipiravir alone, but risks spreading both established and newly emerging mutations, including possible drug resistance mutations, if transmission occurs before the viral populations are eradicated.
genetic hitchhiking, influenza, mutational meltdown, population genetics
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Copyright The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact email@example.com
DOI of Published Version
Genome Biol Evol. 2017 Jul 1;9(7):1913-1924. doi: 10.1093/gbe/evx138. Link to article on publisher's site
Genome biology and evolution
Ormond, Louise; Liu, Ping; Matuszewski, Sebastian; Renzette, Nicholas; Bank, Claudia; Zeldovich, Konstantin B.; Bolon, Daniel N.; Kowalik, Timothy F.; Finberg, Robert W.; Jensen, Jeffrey D.; and Wang, Jennifer P., "The Combined Effect of Oseltamivir and Favipiravir on Influenza A Virus Evolution" (2017). Open Access Articles. 3219.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License