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

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. mutations different evolutionary Thus, this work highlights experimental scenarios of clinical relevance of both successful and failed evolutionary rescue, and allows us to observe the dynamics of mutational meltdown in action. Our results demonstrate the promise of drug-induced mutational meltdown as a means for combating viral populations, and for favipiravir as an effective strategy against IAV in particular. Yet, our findings also raise concerns that proper drug dosage is essential for effective treatment. By discussing our results with respect to concepts from evolutionary theory, we outline prospects for the better prediction of the evolutionary response of pathogens to drug pressure.