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Evidence of the Coevolution of Antigenicity and Host Cell Tropism of Foot-and-Mouth Disease Virus In Vivo

Cecilia Tami,^1, Oscar Taboga,¹ Analía Berinstein,^1,2 José I. Núñez,^3,4 Eduardo L. Palma,^1,2 Esteban Domingo,^3,4 Francisco Sobrino,^3,4* and Elisa Carrillo^1,2*

Instituto de Biotecnología, Centro de Investigación en Ciencias Veterinarias y Agronómicas, INTA,¹ Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina,² Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid,³ CISA-INIA, Valdeolmos, 28130 Madrid, Spain⁴

Received 23 May 2002/ Accepted 8 October 2002

In this work we analyze the antigenic properties and the stability in cell culture of virus mutants recovered upon challenge of peptide-vaccinated cattle with foot-and-mouth disease virus (FMDV) C3 Arg85. Previously, we showed that a significant proportion of 29 lesions analyzed (41%) contained viruses with single amino acid replacements (R141G, L144P, or L147P) within a major antigenic site located at the G-H loop of VP1, known to participate also in interactions with integrin receptors. Here we document that no replacements at this site were found in viruses from 12 lesions developed in six control animals upon challenge with FMDV C3 Arg85. Sera from unprotected, vaccinated animals exhibited poor neutralization titers against mutants recovered from them. Sequence analyses of the viruses recovered upon 10 serial passages in BHK-21 and FBK-2 cells in the presence of preimmune (nonneutralizing) sera revealed that mutants reverted to the parental sequence, suggesting an effect of the amino acid replacements in the interaction of the viruses with cells. Parallel passages in the presence of subneutralizing concentrations of immune homologous sera resulted in the maintenance of mutations R141G and L147P, while mutation L144P reverted to the C3 Arg85 sequence. Reactivity with a panel of FMDV type C-specific monoclonal antibodies indicated that mutant viruses showed altered antigenicity. These results suggest that the selective pressure exerted by host humoral immune response can play a role in both the selection and stability of antigenic FMDV variants and that such variants can manifest alterations in cell tropism.

Present address: National Institutes of Health, Rockville, MD 20852.