Favipiravir elicits antiviral mutagenesis during virus replication in vivo
Open Access
- 21 October 2014
- journal article
- research article
- Published by eLife Sciences Publications, Ltd in eLife
- Vol. 3, e03679
- https://doi.org/10.7554/elife.03679
Abstract
Lethal mutagenesis has emerged as a novel potential therapeutic approach to treat viral infections. Several studies have demonstrated that increases in the high mutation rates inherent to RNA viruses lead to viral extinction in cell culture, but evidence during infections in vivo is limited. In this study, we show that the broad-range antiviral nucleoside favipiravir reduces viral load in vivo by exerting antiviral mutagenesis in a mouse model for norovirus infection. Increased mutation frequencies were observed in samples from treated mice and were accompanied with lower or in some cases undetectable levels of infectious virus in faeces and tissues. Viral RNA isolated from treated animals showed reduced infectivity, a feature of populations approaching extinction during antiviral mutagenesis. These results suggest that favipiravir can induce norovirus mutagenesis in vivo, which in some cases leads to virus extinction, providing a proof-of-principle for the use of favipiravir derivatives or mutagenic nucleosides in the clinical treatment of noroviruses.Keywords
Funding Information
- Wellcome Trust (WT097997MA)
This publication has 67 references indexed in Scilit:
- Influence of genome-scale RNA structure disruption on the replication of murine norovirus—similar replication kinetics in cell culture but attenuation of viral fitness in vivoNucleic Acids Research, 2013
- Coxsackievirus B3 mutator strains are attenuated in vivoProceedings of the National Academy of Sciences of the United States of America, 2012
- Development of a reverse-genetics system for murine norovirus 3: long-term persistence occurs in the caecum and colonJournal of General Virology, 2012
- Ribavirin Can Be Mutagenic for ArenavirusesJournal of Virology, 2011
- Interferons and Ribavirin Effectively Inhibit Norwalk Virus Replication in Replicon-Bearing CellsJournal of Virology, 2007
- Murine Noroviruses Comprising a Single Genogroup Exhibit Biological Diversity despite Limited Sequence DivergenceJournal of Virology, 2007
- In Vitro and In Vivo Activities of T-705 against Arenavirus and Bunyavirus InfectionsAntimicrobial Agents and Chemotherapy, 2007
- Analysis of Ribavirin Mutagenicity in Human Hepatitis C Virus InfectionJournal of Virology, 2007
- Efficacy of Orally Administered T-705 on Lethal Avian Influenza A (H5N1) Virus Infections in MiceAntimicrobial Agents and Chemotherapy, 2007
- Murine Norovirus: a Model System To Study Norovirus Biology and PathogenesisJournal of Virology, 2006