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Journal of Virology, November 2008, p. 10465-10476, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.00825-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Hidden Virulence Determinants in a Viral Quasispecies In Vivo{triangledown}

Marta Sanz-Ramos,1 Fayna Díaz-San Segundo,2,{dagger} Cristina Escarmís,1 Esteban Domingo,1,3 and Noemí Sevilla1,2*

Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Cantoblanco, Madrid 28049, Spain,1 Centro de Investigación en Sanidad Animal, INIA, 28130 Valdeolmos, Madrid, Spain,2 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain3

Received 17 April 2008/ Accepted 2 August 2008

The characterization of virulence determinants of pathogenic agents is of utmost relevance for the design of disease control strategies. So far, two classes of virulence determinants have been characterized for viral populations: those imprinted in the nucleotide sequence of some specific genomic regions and those that depend on the complexity of the viral population as such. Here we provide evidence of a virulence determinant that depends neither on a genomic sequence nor on detectable differences in population complexity. Foot-and-mouth disease virus is lethal for C57BL/6 mice showing the highest viral load in pancreas. Virus isolated from pancreas after one passage in mice showed an attenuated phenotype, with no lethality even at the highest dose tested. By contrast, virus from sera of the same mice displayed a virulence similar to that of the parental wild-type clone and virus isolated from spleen displayed an intermediate phenotype. However, viral populations from pancreas, spleen, and serum showed indistinguishable consensus genomic nucleotide sequences and mutant spectrum complexities, as quantified according to the mutation frequencies of both entire genomic nucleotide sequences of biological clones. The results show that the populations with differing virulences cannot be distinguished either by the consensus sequence or by the average complexity of the mutant spectrum. Differential harvesting of virus generated by cell transfection of RNA from serum and pancreas failed to reveal genetic differences between subpopulations endowed with differing virulences. In addition to providing evidence of hidden virulence determinants, this study underlines the capacity of a clone of an RNA virus to rapidly diversify phenotypically in vivo.

* Corresponding author. Mailing address: Centro de Investigación en Sanidad Animal, CISA-INIA, Ctra. Algete-El Casar s/n, 28130 Valdeolmos, Madrid, Spain. Phone: 34 916202300. Fax: 34 91 6202247. E-mail: sevilla{at}inia.es

{triangledown} Published ahead of print on 20 August 2008.

{dagger} Present address: Plum Island Animal Disease Center, North Atlantic Area, Agricultural Research Service, U.S. Department of Agriculture, Greenport, NY 11944.

Journal of Virology, November 2008, p. 10465-10476, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.00825-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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