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Journal of Virology, October 2001, p. 9723-9730, Vol. 75, No. 20
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.20.9723-9730.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Efficient Virus Extinction by Combinations of a Mutagen and Antiviral Inhibitors

Nonia Pariente,1 Saleta Sierra,1,dagger Pedro R. Lowenstein,2 and Esteban Domingo1,*

Centro de Biología Molecular "Severo Ochoa," Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain,1 and Molecular Medicine Unit, Department of Medicine, University of Manchester, Manchester M13 9PT, United Kingdom2

Received 25 April 2001/Accepted 23 July 2001

The effect of combinations of the mutagenic base analog 5-fluorouracil (FU) and the antiviral inhibitors guanidine hydrochloride (G) and heparin (H) on the infectivity of foot-and-mouth disease virus (FMDV) in cell culture has been investigated. Related FMDV clones differing up to 106-fold in relative fitness in BHK-21 cells have been compared. Systematic extinction of intermediate fitness virus was attained with a combination of FU and G but not with the mutagen or the inhibitor alone. Systematic extinction of high-fitness FMDV required the combination of FU, G, and H. FMDV showing high relative fitness in BHK-21 cells but decreased replicative ability in CHO cells behaved as a low-fitness virus with regard to extinction mutagenesis in CHO cells. This confirms that relative fitness, rather than a specific genomic sequence, determines the FMDV response to enhanced mutagenesis. Mutant spectrum analysis of several genomic regions from a preextinction population showed a statistically significant increase in the number of mutations compared with virus passaged in parallel in the absence of FU and inhibitors. Also, in a preextinction population the types of mutations that can be attributed to the mutagenic action of FU were significantly more frequent than other mutation types. The results suggest that combinations of mutagenic agents and antiviral inhibitors can effectively drive high-fitness virus into extinction.

* Corresponding author. Mailing address: Centro de Biología Molecular "Severo Ochoa," Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain. Phone: 34-91-397 8485. Fax: 34-91-397 4799. E-mail: edomingo{at}cbm.uam.es.

dagger Present address: Institüt für Virologie, Universität zu Köln, 50935 Köln, Germany.

Journal of Virology, October 2001, p. 9723-9730, Vol. 75, No. 20
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.20.9723-9730.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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