THE STRUCTURE AND ANTIGENICITY OF A TYPE-C FOOT-AND-MOUTH-DISEASE VIRUS

Background: Picornaviruses are responsible for a wide range of mammali an diseases and, in common with other RNA viruses, show considerable a ntigenic variation. Foot-and-mouth disease viruses (FMDVs) constitute one genus of the picornavirus family and are classified into seven ser otypes, each of which shows considerable intratypic variation. This an tigenic variation leads to continuing difficulties in controlling the disease. To date the structure of only one serotype, O, has been repor ted. Results: The three-dimensional structure of a serotype C (isolate C-S8c1) FMDV, has been determined crystallographically at 3.5 angstro m resolution. The main chain conformation of the virion is very simila r to that of type O1 virus. The immunodominant G-H loop of VP1, the pr esumed site of cell attachment, is disordered in both types of virus i ndicating a functional role for flexibility of this region. There are significant changes in the structure of other antigenic loops and in s ome internal regions involved in protomer-protomer contacts, including the entire amino-terminal portion of VP2, described here for the firs t time for a picornavirus. Antigenic sites have been identified by gen etic and peptide mapping methods, and located on the capsid. The data reveal a major new discontinuous antigenic site (site D) which is loca ted near to the three-fold axis and involves residues of VP1, VP2 and VP3 which lie adjacent to each other on the capsid. Conclusion: In FMD V type C, amino acid substitutions seen in mutants that are resistant to neutralization by monoclonal antibodies (MAbs) map to predominantly surface-oriented residues with solvent-accessible side-chains not inv olved in interactions with other amino acids, whereas residues which a re accessible but not substituted are found to be more frequently invo lved in protein-protein interactions. This provides a molecular interp retation for the repeated isolation of the same amino acid substitutio ns in MAb-resistant variants, an observation frequently made with RNA viruses. This first comparison of two FMDV serotypes shows how subtle changes at antigenic sites are sufficient to cause large changes in an tigenic specificity between serotypes.