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Journal of Virology, October 2009, p. 10140-10151, Vol. 83, No. 19
0022-538X/09/$08.00+0     doi:10.1128/JVI.00903-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Systematic Study of the Genetic Response of a Variable Virus to the Introduction of Deleterious Mutations in a Functional Capsid Region{triangledown}

Eva Luna, Alicia Rodríguez-Huete, Verónica Rincón, Roberto Mateo,{dagger} and Mauricio G. Mateu*

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

Received 6 May 2009/ Accepted 11 July 2009

We have targeted the intersubunit interfaces in the capsid of foot-and-mouth disease virus to investigate the genetic response of a variable virus when individual deleterious mutations are systematically introduced along a functionally defined region of its genome. We had previously found that the individual truncation (by mutation to alanine) of 28 of the 42 amino acid side chains per protomer involved in interactions between capsid pentameric subunits severely impaired infectivity. We have now used viral RNAs individually containing each of those 28 deleterious mutations (or a few others) to carry out a total of 96 transfections of susceptible cells, generally followed by passage(s) of the viral progeny in cell culture. The results revealed a very high frequency of fixation in the capsid of second-site, stereochemically diverse substitutions that compensated for the detrimental effect of primary substitutions at many different positions. Most second-site substitutions occurred at or near the capsid interpentamer interfaces and involved residues that are spatially very close to the originally substituted residue. However, others occurred far from the primary substitution, and even from the interpentamer interfaces. Remarkably, most second-site substitutions involved only a few capsid residues, which acted as "second-site hot spots." Substitutions at these hot spots compensated for the deleterious effects of many different replacements at diverse positions. The remarkable capacity of the virus to respond to the introduction of deleterious mutations in the capsid with the frequent fixation of diverse second-site mutations, and the existence of second-site hot spots, may have important implications for virus evolution.

* Corresponding author. Mailing address: Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain. Phone: 34-91-1964575. Fax: 34-91-1964420. E-mail: mgarcia{at}cbm.uam.es

{triangledown} Published ahead of print on 22 July 2009.

{dagger} Present address: Microbiology and Immunology Department, Stanford University, Fairchild Science Building, 299 Campus Drive, D-300, Stanford, CA 94305-5124.

Journal of Virology, October 2009, p. 10140-10151, Vol. 83, No. 19
0022-538X/09/$08.00+0     doi:10.1128/JVI.00903-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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