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Journal of Virology, February 2007, p. 2012-2024, Vol. 81, No. 4
0022-538X/07/$08.00+0     doi:10.1128/JVI.01606-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Foot-and-Mouth Disease Virus Mutant with Decreased Sensitivity to Ribavirin: Implications for Error Catastrophe{triangledown}

Macarena Sierra, Antero Airaksinen,{dagger} Claudia González-López, Rubén Agudo, Armando Arias, and Esteban Domingo*

Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, E-28049 Madrid, Spain

Received 27 July 2006/ Accepted 23 November 2006

The nucleoside analogue ribavirin (R) is mutagenic for foot-and-mouth disease virus (FMDV). Passage of FMDV in the presence of increasing concentrations of R resulted in the selection of FMDV with the amino acid substitution M296I in the viral polymerase (3D). Measurements of progeny production and viral fitness with chimeric viruses in the presence and absence of R documented that the 3D substitution M296I conferred on FMDV a selective replicative advantage in the presence of R but not in the absence of R. In polymerization assays, a purified mutant polymerase with I296 showed a decreased capacity to use ribavirin triphosphate as a substrate in the place of GTP and ATP, compared with the wild-type enzyme. The results suggest that M296I has been selected because it attenuates the mutagenic activity of R with FMDV. Replacement M296I is located within a highly conserved stretch in picornaviral polymerases which includes residues that interact with the template-primer complex and probably also with the incoming nucleotide, according to the three-dimensional structure of FMDV 3D. Given that a 3D substitution, distant from M296I, was associated with resistance to R in poliovirus, the results indicate that picornaviral polymerases include different domains that can alter the interaction of the enzyme with mutagenic nucleoside analogues. Implications for lethal mutagenesis are discussed.

* Corresponding author. Mailing address: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, E-28049 Madrid, Spain. Phone: 34 91 4978485. Fax: 34 91 4974799. E-mail: edomingo{at}cbm.uam.es.

{triangledown} Published ahead of print on 6 December 2006.

{dagger} Present address: National Product Control Agency for Welfare and Health, Chemicals Unit, PL 210, FI-00531 Helsinki, Finland.

Present address: Cell Biology Unit, MRC-Laboratory for Molecular Cell Biology, and Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom.

Journal of Virology, February 2007, p. 2012-2024, Vol. 81, No. 4
0022-538X/07/$08.00+0     doi:10.1128/JVI.01606-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Arias, A., Arnold, J. J., Sierra, M., Smidansky, E. D., Domingo, E., Cameron, C. E. (2008). Determinants of RNA-Dependent RNA Polymerase (In)fidelity Revealed by Kinetic Analysis of the Polymerase Encoded by a Foot-and-Mouth Disease Virus Mutant with Reduced Sensitivity to Ribavirin. J. Virol. 82: 12346-12355 [Abstract] [Full Text]  
  • Sanz-Ramos, M., Diaz-San Segundo, F., Escarmis, C., Domingo, E., Sevilla, N. (2008). Hidden Virulence Determinants in a Viral Quasispecies In Vivo. J. Virol. 82: 10465-10476 [Abstract] [Full Text]  
  • Nunez, J. I., Molina, N., Baranowski, E., Domingo, E., Clark, S., Burman, A., Berryman, S., Jackson, T., Sobrino, F. (2007). Guinea Pig-Adapted Foot-and-Mouth Disease Virus with Altered Receptor Recognition Can Productively Infect a Natural Host. J. Virol. 81: 8497-8506 [Abstract] [Full Text]  
  • Ferrer-Orta, C., Arias, A., Perez-Luque, R., Escarmis, C., Domingo, E., Verdaguer, N. (2007). Sequential structures provide insights into the fidelity of RNA replication. Proc. Natl. Acad. Sci. USA 104: 9463-9468 [Abstract] [Full Text]  


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