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

View ORCID ProfileClaudia Bank, Nicholas Renzette, Ping Liu, View ORCID ProfileSebastian Matuszewski, Hyunjin Shim, View ORCID ProfileMatthieu Foll, View ORCID ProfileDaniel N. A. Bolon, Konstantin B. Zeldovich, Timothy F. Kowalik, Robert W. Finberg, View ORCID ProfileJennifer P. Wang, Jeffrey D. Jensen
doi: https://doi.org/10.1101/048934
Claudia Bank
*School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
†Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland
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Nicholas Renzette
‡Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, USA
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Ping Liu
§Department of Medicine, University of Massachusetts Medical School, Worcester, USA
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Sebastian Matuszewski
*School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
†Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland
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Hyunjin Shim
*School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
†Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland
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Matthieu Foll
*School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
†Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland
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Daniel N. A. Bolon
††Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, USA
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Konstantin B. Zeldovich
§§Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, USA
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Timothy F. Kowalik
‡Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, USA
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Robert W. Finberg
§Department of Medicine, University of Massachusetts Medical School, Worcester, USA
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Jennifer P. Wang
§Department of Medicine, University of Massachusetts Medical School, Worcester, USA
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  • For correspondence: jennifer.wang@umassmed.edu jeffrey.jensen@epfl.ch
Jeffrey D. Jensen
*School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
†Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland
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  • For correspondence: jennifer.wang@umassmed.edu jeffrey.jensen@epfl.ch
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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 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.

Footnotes

  • ABBREVIATIONS: MDCK, Madin-Darby Canine Kidney; WFABC, Wright-Fisher Approximate Bayesian Computation; CP-WFABC, change-point WFABC; MOI, multiplicity of infection; PFU, plaque forming units; WSHRI, weak-selection Hill-Robertson interference; RdRp, RNA-dependent RNA polymerase; NP, nucleoprotein; CPE, cytopathic effect; ED50, 50% effective dose; IAV, influenza A virus

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 02, 2016.
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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 D. Jensen
bioRxiv 048934; doi: https://doi.org/10.1101/048934
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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 D. Jensen
bioRxiv 048934; doi: https://doi.org/10.1101/048934

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