Browsing by keyword "mutational meltdown"
Now showing items 1-3 of 3
-
An experimental evaluation of drug-induced mutational meltdown 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 utilize 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.
-
Imposed mutational meltdown as an antiviral strategyFollowing widespread infections of the most recent coronavirus known to infect humans, SARS-CoV-2, attention has turned to potential therapeutic options. With no drug or vaccine yet approved, one focal point of research is to evaluate the potential value of repurposing existing antiviral treatments, with the logical strategy being to identify at least a short-term intervention to prevent within-patient progression, whilst long-term vaccine strategies unfold. Here, we offer an evolutionary / population-genetic perspective on one approach that may overwhelm the capacity for pathogen defense (i.e., adaptation) - induced mutational meltdown - providing an overview of key concepts, review of previous theoretical and experimental work of relevance, and guidance for future research. Applied with appropriate care, including target specificity, induced mutational meltdown may provide a general, rapidly implemented approach for the within-patient eradication of a wide range of pathogens or other undesirable microorganisms.
-
The Combined Effect of Oseltamivir and Favipiravir on Influenza A Virus EvolutionInfluenza 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.
