Nature 347, 569 - 572 (11 October 1990); doi:10.1038/347569a0

Structural and serological evidence for a novel mechanism of antigenic variation in foot-and-mouth disease virus

Nigel Parry^*, Graham Fox^*, David Rowlands^*, Fred Brown^*§, Elizabeth Fry^†, Ravindra Acharya^†§, Derek Logan^† & David Stuart^†‡

^*Department of Virology, Wellcome Biotech, Langley Court, Beckenham, Kent BR3 3BS, UK
^†Laboratory of Molecular Biophysics, The Rex Richards Building, South Parks Road, Oxford OX1 3QU, UK
^‡To whom correspondence should be addressed.
^§Present addresses: Yale University School of Medicine, New Haven, Connecticut 06520, USA (FB); Department of Biochemistry, 4-West, University of Bath, Claverton Down, Bath. BA2 7AY, UK (R.A.)

CHANGES resulting in altered antigenic properties of viruses nearly always occur on their surface and have been attributed to the substitution of residues directly involved in binding antibody. To investigate the mechanism of antigenic variation in foot-and-mouth disease virus (FMDV), variants that escape neutralization by a monoclonal antibody have been compared crystallographically and serologically with parental virus. FMDVs form one of the four genera of the Picornaviridae. The unenveloped icosahedral shell comprises 60 copies each of four structural proteins VP1–4. Representatives from each of the genera have similar overall structure, but differences in the external features^1–4. For example, human rhinovirus has a pronounced 'canyon' that is proposed to contain the cell attachment site^1,5–7, whereas elements of the attachment site for FMDV, which involves the G–H loop (residues 134–160) and C-terminus (200–213) of VP1^8,9, are exposed on the surface. Moreover, this G–H loop, which is a major antigenic site of FMDV, forms a prominent, highly accessible protrusion⁴, a feature not seen in other picornaviruses. It is this loop that is perturbed in the variant viruses that we have studied. The amino acid mutations characterizing the variants are not at positions directly involved in antibody binding, but result in far-reaching perturbations of the surface structure of the virus. Thus, this virus seems to use a novel escape mechanism whereby an induced confor-mational change in a major antigenic loop destroys the integrity of the epitope.

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