Potential benefits of sequential inhibitor-mutagen treatments of RNA virus infections
Authors: Hector Tejero
Susanna C Manrubia
Celia Perales
Rubén Agudo
Esteban Domingo
Journal: PLoS Pathogens (2009)
Discipline: MICROBIOLOGY
Keywords: Lethal mutagenesis; antiviral strategy; virus extinction; enhanced mutagenesis; inhibitor-resistant virus mutants
Affiliations: Departamento de Virología y Microbiología, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.

Abstract:  Lethal mutagenesis is an antiviral strategy consisting of virus extinction associated with enhanced mutagenesis. The use of non-mutagenic antiviral inhibitors has faced the problem of selection of inhibitor-resistant virus mutants. Quasispecies dynamics predicts, and clinical results have confirmed, that combination therapy has an advantage over monotherapy to delay or prevent selection of inhibitor-escape mutants. Using ribavirin-mediated mutagenesis of foot-and-mouth disease virus (FMDV), here we show that, contrary to expectations, sequential administration of the antiviral inhibitor guanidine (GU) first, followed by ribavirin, is more effective than combination therapy with the two drugs, or than either drug used individually. Coelectroporation experiments suggest that limited inhibition of replication of interfering mutants by GU may contribute to the benefits of the sequential treatment. In lethal mutagenesis, a sequential inhibitor-mutagen treatment can be more effective than the corresponding combination treatment to drive a virus towards extinction. Such an advantage is also supported by a theoretical model for the evolution of a viral population under the action of increased mutagenesis in the presence of an inhibitor of viral replication. The model suggests that benefits of the sequential treatment are due to the involvement of a mutagenic agent, and to competition for susceptible cells exerted by the mutant spectrum. The results may impact lethal mutagenesis-based protocols, as well as current antiviral therapies involving ribavirin. 

Retracted: No

PubPeer comments:
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 Fig 4J. ![file] Increasing the contrast reveals curiously repetitive areas in the background. Fig 2F. More areas of repeated background, at different scales. ![file] , 
 Retracted [19 November 2021] . -------------------------- This article has been retracted: please see Elsevier Policy on Article Withdrawal . Several figures presented in the manuscript appear to have been doctored. Figure 2B copied areas from figure 2C in the publication Gene 675 (2018) 102-109 https: doi.org 10.1016 j.gene.2018.06.095 At higher contrast, the western blots in Figures 2F, 4F, and 4J show signs of image manipulation. The journal has tried to contact the authors of this article. As there is no explanation for the image manipulations, the Editors-in-Chief of Gene have lost confidence in the validity of this work and have decided to retract it. ,