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Journal of Virology, December 1998, p. 10171-10179, Vol. 72, No. 12
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Rapid Selection in Modified BHK-21 Cells of a Foot-and-Mouth Disease Virus Variant Showing Alterations in Cell Tropism

Cristina Escarmís,1 Elisa C. Carrillo,2 Marcela Ferrer,3 Juan F. García Arriaza,1 Nora Lopez,3 Cecilia Tami,2 Nuria Verdaguer,4 Esteban Domingo,1,* and Maria T. Franze-Fernández3,*

Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Universidad Autónoma de Madrid, 28049 Madrid, Spain1; Instituto de Biotecnología, Centro de Investigación en Ciencias Veterinarias, INTA 1708 Morón, Buenos Aires,2 and Centro de Virología Animal (CONICET), Serrano 669, 1414 Buenos Aires,3 Argentina; and Centre de Investigació i Desenvolupament (CSIC), Jordi Girona 6, 08028 Barcelona, Spain4

Received 26 June 1998/Accepted 9 September 1998

With persistent foot-and-mouth disease virus (FMDV) in BHK-21 cells, there is coevolution of the cells and the resident virus; the virulence of the virus for the parental BHK-21 cells is gradually increased, and the cells become partially resistant to FMDV. Here we report that variants of FMDV C3Arg/85 were selected in a single infection of partially resistant BHK-21 cells (termed BHK-Rb cells). Indirect immunofluorescence showed that the BHK-Rb cell population was heterogeneous with regard to susceptibility to C3Arg/85 infection. Infection of BHK-Rb cells with C3Arg/85 resulted in an early phase of partial cytopathology which was followed at 6 to 10 days postinfection by the shedding of mutant FMDVs, termed C3-Rb. The selected C3-Rb variants showed increased virulence for BHK-21 cells, were able to overcome the resistance of modified BHK-21 cells to infection, and had acquired the ability to bind heparin and to infect wild-type Chinese hamster ovary (CHO) cells. A comparison of the genomic sequences of the parental and modified viruses revealed only two amino acid differences, located at the surface of the particle, at the fivefold axis of the viral capsid (Asp-9right-arrowAla in VP3 and either Gly-110right-arrowArg or His-108right-arrowArg in VP1). The same phenotypic and genotypic modifications occurred in a highly reproducible manner; they were seen in a number of independent infections of BHK-Rb cells with viral preparation C3Arg/85 or with clones derived from it. Neither amino acid substitutions in other structural or nonstructural proteins nor nucleotide substitutions in regulatory regions were found. These results prove that infection of partially permissive cells can promote the rapid selection of virus variants that show alterations in cell tropism and are highly virulent for the same cells.

* Corresponding author. Mailing address for Esteban Domingo: Centro de Biología Molecular "Severo Ochoa," Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain. Phone: 34-91-3978485. Fax: 34-91-3974799. E-mail: edomingo{at}cbm.uam.es. Mailing address for Maria T. Franze-Fernández: Centro de Virología Animal, Serrano 669, 1414 Buenos Aires, Argentina. Phone and fax: 54-1-825-1863. E-mail: MTFF{at}cevan.sld.ar.

Journal of Virology, December 1998, p. 10171-10179, Vol. 72, No. 12
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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