STRUCTURAL COMPARISON OF 2 STRAINS OF FOOT-AND-MOUTH-DISEASE VIRUS SUBTYPE-O-1 AND A LABORATORY ANTIGENIC VARIANT, G67

Background: Foot-and-mouth disease viruses (FMDVs) are members of the picornavirus family and cause an economically important disease of clo ven-hoofed animals. To understand the structural basis of antigenic va riation in FMDV, we have determined the structures of two viruses clos ely related to strain O1BFS whose structure is known. Results: The two new structures are, like O1BFS, both serotype O viruses. The first, O -1 Kaufbeuren (O1K), is a field isolate dating from an outbreak of FMD in Europe in the 1960s. The second, called G67, is a quadruple mutant of O1K, generated in the laboratory, that bears point mutations confe rring resistance to neutralization by monoclonal antibodies, specific for each of the four major antigenic sites defined previously. The ava ilability of the three related virus structures permits a detailed ana lysis of the way amino acid substitutions influence antigenicity. Stru ctural changes are seen to be limited, in general, to the substituted side chain. For example, the GH loop of VP1, a highly antigenic and mo bile protuberance which becomes ordered only under reducing conditions , was essentially indistinguishable in the three viruses despite the a ccumulation of up to four changes within its 15-residue sequence. At o ne of the other antigenic sites, however, changes between the two fiel d strains did perturb both side-chain and main-chain structures in the vicinity. Conclusions: The conservation of conformation of the GH loo p of VP1 adds to the evidence implicating an integrin as the cellular receptor for FMDV, since this loop contains a conserved RGD (Arg-Gly-A sp) sequence structurally similar to the same tripeptide in some other integrin-binding proteins. Structural changes required for the virus to escape neutralization by monoclonal antibodies are generally small. The more extensive type of structural change exhibited by the Geld is olates probably reflects differing selective pressures operating in vi vo and in vitro.