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

11 Scopus citations

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

ASJC Scopus subject areas

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

Fingerprint Dive into the research topics of 'An experimental evaluation of drug-induced mutational meltdown as an antiviral treatment strategy'. Together they form a unique fingerprint.

  • Cite this

    Bank, C., Renzette, N., Liu, P., Matuszewski, S., Shim, H., Foll, M., Bolon, D. N. A., Zeldovich, K. B., Kowalik, T. F., Finberg, R. W., Wang, J. P., & Jensen, J. (2016). An experimental evaluation of drug-induced mutational meltdown as an antiviral treatment strategy. Evolution, 70(11), 2470-2484. https://doi.org/10.1111/evo.13041