Antigenically profound amino acid substitutions occur during large population passages of foot-and-mouth disease virus.

Foot-and-mouth disease virus (FMDV) with amino acid substitutions next to the highly conserved R-G-D motif were isolated following large population passages of the virus (N. Sevilla and E. Domingo, 1996, J. Virol., in press). Reactivity with a panel of monoclonal antibodies which recognize different epitopes within site A was abolished or highly diminished in the mutants. This provides direct evidence of a drastic antigenic change occurring in the absence of selection by antibodies. Molecular modeling studies predict only minor alterations in the conformation of the G-H loop of VP1 and the R-G-D motif in these mutants. None of these variants became dominant in many serial infections involving smaller FMDV population numbers. In addition to documenting profound antigenic variation without immune selection, the results suggest that the repertoire of antigenic variants evolving in viral quasispecies may be greatly influenced by the population size of the virus.