The combined effect of oseltamivir and favipiravir on influenza a virus evolution

Louise Ormond, Ping Liu, Sebastian Matuszewski, Nicholas Renzette, Claudia Bank, Konstantin Zeldovich, Daniel N. Bolon, Timothy F. Kowalik, Robert W. Finberg, Jeffrey Jensen, Jennifer P. Wang

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1913-1924
Number of pages12
JournalGenome Biology and Evolution
Volume9
Issue number7
DOIs
StatePublished - Jul 1 2017

Fingerprint

Oseltamivir
influenza
Orthomyxoviridae
mutation
virus
Influenza A virus
Mutation
antiviral agents
Population
Genome
drug
genome
Antiviral Agents
extinction
Genetic Drift
drug resistance
Mutation Rate
Drug Resistance
genetic drift
Human Influenza

Keywords

  • Genetic hitchhiking
  • Influenza
  • Mutational meltdown
  • Population genetics

ASJC Scopus subject areas

  • Medicine(all)
  • Ecology, Evolution, Behavior and Systematics
  • Genetics

Cite this

Ormond, L., Liu, P., Matuszewski, S., Renzette, N., Bank, C., Zeldovich, K., ... Wang, J. P. (2017). The combined effect of oseltamivir and favipiravir on influenza a virus evolution. Genome Biology and Evolution, 9(7), 1913-1924. https://doi.org/10.1093/gbe/evx138

The combined effect of oseltamivir and favipiravir on influenza a virus evolution. / Ormond, Louise; Liu, Ping; Matuszewski, Sebastian; Renzette, Nicholas; Bank, Claudia; Zeldovich, Konstantin; Bolon, Daniel N.; Kowalik, Timothy F.; Finberg, Robert W.; Jensen, Jeffrey; Wang, Jennifer P.

In: Genome Biology and Evolution, Vol. 9, No. 7, 01.07.2017, p. 1913-1924.

Research output: Contribution to journalArticle

Ormond, L, Liu, P, Matuszewski, S, Renzette, N, Bank, C, Zeldovich, K, Bolon, DN, Kowalik, TF, Finberg, RW, Jensen, J & Wang, JP 2017, 'The combined effect of oseltamivir and favipiravir on influenza a virus evolution', Genome Biology and Evolution, vol. 9, no. 7, pp. 1913-1924. https://doi.org/10.1093/gbe/evx138
Ormond L, Liu P, Matuszewski S, Renzette N, Bank C, Zeldovich K et al. The combined effect of oseltamivir and favipiravir on influenza a virus evolution. Genome Biology and Evolution. 2017 Jul 1;9(7):1913-1924. https://doi.org/10.1093/gbe/evx138
Ormond, Louise ; Liu, Ping ; Matuszewski, Sebastian ; Renzette, Nicholas ; Bank, Claudia ; Zeldovich, Konstantin ; Bolon, Daniel N. ; Kowalik, Timothy F. ; Finberg, Robert W. ; Jensen, Jeffrey ; Wang, Jennifer P. / The combined effect of oseltamivir and favipiravir on influenza a virus evolution. In: Genome Biology and Evolution. 2017 ; Vol. 9, No. 7. pp. 1913-1924.
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