RT Journal Article SR Electronic T1 An experimental evaluation of drug-induced mutational meltdown as an antiviral treatment strategy JF bioRxiv FD Cold Spring Harbor Laboratory SP 048934 DO 10.1101/048934 A1 Claudia Bank A1 Nicholas Renzette A1 Ping Liu A1 Sebastian Matuszewski A1 Hyunjin Shim A1 Matthieu Foll A1 Daniel N.A. Bolon A1 Konstantin B. Zeldovich A1 Timothy F. Kowalik A1 Robert W. Finberg A1 Jennifer P. Wang A1 Jeffrey D. Jensen YR 2016 UL http://biorxiv.org/content/early/2016/04/16/048934.abstract AB 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 utilized an experimental evolution framework, combined with novel population genetic method development for inference from time-sampled data, in order to evaluate the effectiveness of favipiravir against IAV. Evaluating whole genome polymorphism data across fifteen time points under multiple drug concentrations and in controls, we present the first evidence for the ability of viral 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.