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dc.contributor.authorBank, Claudia
dc.contributor.authorRenzette, Nicholas
dc.contributor.authorLiu, Ping
dc.contributor.authorMatuszewski, Sebastian
dc.contributor.authorShim, Hyunjin
dc.contributor.authorFoll, Matthieu
dc.contributor.authorBolon, Daniel N.
dc.contributor.authorZeldovich, Konstantin B.
dc.contributor.authorKowalik, Timothy F.
dc.contributor.authorFinberg, Robert W.
dc.contributor.authorWang, Jennifer P.
dc.contributor.authorJensen, Jeffrey D.
dc.date2022-08-11T08:08:23.000
dc.date.accessioned2022-08-23T15:53:14Z
dc.date.available2022-08-23T15:53:14Z
dc.date.issued2016-06-02
dc.date.submitted2018-06-13
dc.identifier.citation<p>bioRxiv 048934; doi: https://doi.org/10.1101/048934. <a href="https://doi.org/10.1101/048934" target="_blank">Link to preprint on bioRxiv service.</a></p>
dc.identifier.doi10.1101/048934
dc.identifier.urihttp://hdl.handle.net/20.500.14038/29313
dc.description.abstractThe 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.
dc.language.isoen_US
dc.relation<p>Now published in Evolution doi: <a href="http://dx.doi.org/10.1111/evo.13041" target="_blank">10.1111/evo.13041</a></p>
dc.rightsThe copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectevolutionary biology
dc.subjectinfluenza A virus. drug resistance
dc.subjectfavipiravir
dc.subjectRNA
dc.subjectantiviral drugs
dc.subjectmutational meltdown
dc.subjectEcology and Evolutionary Biology
dc.subjectGenetic Phenomena
dc.subjectImmunology and Infectious Disease
dc.subjectPharmaceutical Preparations
dc.subjectTherapeutics
dc.subjectViruses
dc.titleAn experimental evaluation of drug-induced mutational meltdown as an antiviral treatment strategy [preprint]
dc.typePreprint
dc.source.journaltitlebioRxiv
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2545&amp;context=faculty_pubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/1539
dc.identifier.contextkey12307559
refterms.dateFOA2022-08-23T15:53:14Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathfaculty_pubs/1539
dc.contributor.departmentProgram in Bioinformatics and Integrative Biology
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.contributor.departmentDepartment of Medicine, Division of Infectious Diseases and Immunology
dc.contributor.departmentDepartment of Microbiology and Physiological Systems


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The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.
Except where otherwise noted, this item's license is described as The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.