title: An experimental evaluation of drug-induced mutational meltdown as an antiviral treatment strategy.
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.
authors: School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.|Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.|Current Adrress: Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
authors: Claudia
authors: C
authors: Bank
authors: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, 01605.
authors: Nicholas
authors: N
authors: Renzette
authors: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, 01605.
authors: Ping
authors: P
authors: Liu
authors: School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.|Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
authors: Sebastian
authors: S
authors: Matuszewski
authors: School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.|Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
authors: Hyunjin
authors: H
authors: Shim
authors: School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.|Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.|Current Address: Genetic Cancer Susceptibility, International Agency for Research on Cancer, Lyon, France.
authors: Matthieu
authors: M
authors: Foll
authors: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, 01605.
authors: Daniel N A
authors: DN
authors: Bolon
authors: Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, Massachusetts, 01605.
authors: Konstantin B
authors: KB
authors: Zeldovich
authors: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, 01605.
authors: Timothy F
authors: TF
authors: Kowalik
authors: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, 01605.
authors: Robert W
authors: RW
authors: Finberg
authors: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, 01605. jennifer.wang@umassmed.edu.
authors: Jennifer P
authors: JP
authors: Wang
authors: School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. jeffrey.jensen@epfl.ch.|Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland. jeffrey.jensen@epfl.ch.|Current Address: School of Life Sciences, Arizona State University, Tempe, Arizona, 85287. jeffrey.jensen@epfl.ch.
authors: Jeffrey D
authors: JD
authors: Jensen
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D044966:Anti-Retroviral Agents / Q000494:pharmacology*; D004285:Dogs; D024882:Drug Resistance, Viral / Q000235:genetics*; D019143:Evolution, Molecular; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000235:genetics*; D061985:Madin Darby Canine Kidney Cells; D059645:Mutation Rate; D011110:Polymorphism, Genetic; D011719:Pyrazines / Q000494:pharmacology*
chemical_list: D000577:Amides; D044966:Anti-Retroviral Agents; D011719:Pyrazines; C462182:favipiravir