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Determining the mutation bias of favipiravir in influenza using next-generation sequencing

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Title: Determining the mutation bias of favipiravir in influenza using next-generation sequencing
Authors: Goldhill, DH
Langat, P
Xie, H
Galiano, M
Miah, S
Kellam, P
Zambon, M
Lackenby, A
Barclay, W
Item Type: Journal Article
Abstract: Favipiravir is a broad-spectrum antiviral drug that may be used to treat influenza. Previous research has identified that favipiravir likely acts as a mutagen but the precise mutation bias that favipiravir induces in influenza virus RNAs has not been described. Here, we use next-generation sequencing (NGS) with barcoding of individual RNA molecules to accurately and quantitatively detect favipiravir-induced mutations and to sample orders of magnitude more mutations than would be possible through Sanger sequencing. We demonstrate that favipiravir causes mutations and show that favipiravir primarily acts as a guanine analogue and secondarily as an adenine analogue resulting in the accumulation of transition mutations. We also use a standard NGS pipeline to show that the mutagenic effect of favipiravir can be measured by whole genome sequencing of virus.IMPORTANCE New antiviral drugs are needed as a first line of defence in the event of a novel influenza pandemic. Favipiravir is a broad-spectrum antiviral which is effective against influenza. The exact mechanism of how favipiravir works to inhibit influenza is still unclear. We used next-generation sequencing (NGS) to demonstrate that favipiravir causes mutations in influenza RNA. The greater depth of NGS sequence information over traditional sequencing methods allowed us to precisely determine the bias of particular mutations caused by favipiravir. NGS can also be used in a standard diagnostic pipeline to show that favipiravir is acting on the virus by revealing the mutation bias pattern typical to the drug. Our work will aid in testing whether viruses are resistant to favipiravir and may help demonstrate the effect of favipiravir on viruses in a clinical setting. This will be important if favipiravir is used during a future influenza pandemic.
Issue Date: 4-Jan-2019
Date of Acceptance: 1-Oct-2018
URI: http://hdl.handle.net/10044/1/64789
DOI: https://dx.doi.org/10.1128/JVI.01217-18
ISSN: 1098-5514
Publisher: American Society for Microbiology
Journal / Book Title: Journal of Virology
Volume: 93
Issue: 2
Copyright Statement: © 2018 Goldhill et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/).
Keywords: Science & Technology
Life Sciences & Biomedicine
Virology
favipiravir
mutation bias
next-generation sequencing
Primer ID
influenza
T-705 FAVIPIRAVIR
LETHAL MUTAGENESIS
INFECTION
TRANSMISSION
OSELTAMIVIR
RESISTANCE
MECHANISM
FERRETS
06 Biological Sciences
07 Agricultural And Veterinary Sciences
11 Medical And Health Sciences
Publication Status: Published
Conference Place: United States
Article Number: e01217
Online Publication Date: 2018-10-31
Appears in Collections:National Heart and Lung Institute
Department of Medicine
Faculty of Medicine



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