An experimental evaluation of drug-induced mutational meltdown as an antiviral treatment strategy

Claudia Bank, Nicholas Renzette, Ping Liu, Sebastian Matuszewski, Hyunjin Shim, Matthieu Foll, Daniel N A Bolon, Konstantin B. Zeldovich, Timothy F. Kowalik, Robert W. Finberg, Jennifer P. Wang, Jeffrey Jensen

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

The rapid evolution of drug resistance remains a critical public health concern. The treatment of influenza A virus (IAV) has proven particularly challenging, due to the ability of the virus to develop resistance against current antivirals and vaccines. Here, we evaluate a novel antiviral drug therapy, favipiravir, for which the mechanism of action in IAV involves an interaction with the viral RNA-dependent RNA polymerase resulting in an effective increase in the viral mutation rate. We used an experimental evolution framework, combined with novel population genetic method development for inference from time-sampled data, to evaluate the effectiveness of favipiravir against IAV. Evaluating whole genome polymorphism data across 15 time points under multiple drug concentrations and in controls, we present the first evidence for the ability of IAV populations to effectively adapt to low concentrations of favipiravir. In contrast, under high concentrations, we observe population extinction, indicative of mutational meltdown. We discuss the observed dynamics with respect to the evolutionary forces at play and emphasize the utility of evolutionary theory to inform drug development.

Original languageEnglish (US)
Pages (from-to)2470-2484
Number of pages15
JournalEvolution
Volume70
Issue number11
DOIs
StatePublished - Nov 1 2016

Fingerprint

drug evaluation
Drug Evaluation
Influenza A virus
influenza
Antiviral Agents
virus
drug
RNA-directed RNA polymerase
RNA
antiviral agents
RNA Replicase
drugs
drug development
Viral RNA
Population Genetics
drug resistance
Mutation Rate
Therapeutics
Drug Resistance
evolutionary theory

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Agricultural and Biological Sciences(all)

Cite this

An experimental evaluation of drug-induced mutational meltdown as an antiviral treatment strategy. / Bank, Claudia; Renzette, Nicholas; Liu, Ping; Matuszewski, Sebastian; Shim, Hyunjin; Foll, Matthieu; Bolon, Daniel N A; Zeldovich, Konstantin B.; Kowalik, Timothy F.; Finberg, Robert W.; Wang, Jennifer P.; Jensen, Jeffrey.

In: Evolution, Vol. 70, No. 11, 01.11.2016, p. 2470-2484.

Research output: Contribution to journalArticle

Bank, C, Renzette, N, Liu, P, Matuszewski, S, Shim, H, Foll, M, Bolon, DNA, Zeldovich, KB, Kowalik, TF, Finberg, RW, Wang, JP & Jensen, J 2016, 'An experimental evaluation of drug-induced mutational meltdown as an antiviral treatment strategy', Evolution, vol. 70, no. 11, pp. 2470-2484. https://doi.org/10.1111/evo.13041
Bank C, Renzette N, Liu P, Matuszewski S, Shim H, Foll M et al. An experimental evaluation of drug-induced mutational meltdown as an antiviral treatment strategy. Evolution. 2016 Nov 1;70(11):2470-2484. https://doi.org/10.1111/evo.13041
Bank, Claudia ; Renzette, Nicholas ; Liu, Ping ; Matuszewski, Sebastian ; Shim, Hyunjin ; Foll, Matthieu ; Bolon, Daniel N A ; Zeldovich, Konstantin B. ; Kowalik, Timothy F. ; Finberg, Robert W. ; Wang, Jennifer P. ; Jensen, Jeffrey. / An experimental evaluation of drug-induced mutational meltdown as an antiviral treatment strategy. In: Evolution. 2016 ; Vol. 70, No. 11. pp. 2470-2484.
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