Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 407, Issue 1, Pages 60-78Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2011.01.026
Keywords
virus evolution; quasispecies; foot-and-mouth disease virus; ribavirin; escape mutants
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Funding
- Ministerio de Ciencia e Innovacion [BFU2008-02816/BMC, FIS2008-05273]
- Proyecto Intramural de Frontera del Consejo Superior de Investigaciones Cientificas [200820FO191]
- FIPSE [36558/06]
- Fundacion Ramon Areces
- Comunidad Autonoma de Madrid [S2009-ESP-1601]
- Instituto de Salud Carlos III
- Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas
- Comunidad Autonoma de Madrid
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Lethal mutagenesis is an antiviral strategy that aims to extinguish viruses as a consequence of enhanced mutation rates during virus replication. The molecular mechanisms that underlie virus extinction by mutagenic nucleoside analogues are not well understood. When mutagenic agents and antiviral inhibitors are administered sequentially or in combination, interconnected and often conflicting selective constraints can influence the fate of the virus either towards survival through selection of mutagen-escape or inhibitor-escape mutants or towards extinction. Here we report a study involving the mutagenesis of foot-and-mouth disease virus (FMDV) by the nucleoside analogue ribavirin (R) and the effect of R-mediated mutagenesis on the selection of FMDV mutants resistant to the inhibitor of RNA replication, guanidine hydrochloride (GU). The results show that under comparable (and low) viral load, an inhibitory activity by GU could not substitute for an equivalent inhibitory activity by R in driving FMDV to extinction. Both the prior history of R mutagenesis and the viral population size influenced the selection of GU-escape mutants. A sufficiently low viral load allowed continued viral replication without selection of inhibitor-escape mutants, irrespective of the history of mutagenesis. These observations imply that reductions of viral load as a result of a mutagenic treatment may provide an opportunity either for immune-mediated clearing of a virus or for an alternative antiviral intervention, even if extinction is not initially achieved. (C) 2011 Published by Elsevier Ltd.
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