A single amino acid substitution in nonstructural protein 3A can mediate adaptation of foot-and-mouth disease virus to the guinea pig

The genetic changes selected during the adaptation of a clonal population o f foot-and-mouth disease virus (FMDV) to the guinea pig have been analyzed. FMDV clone C-S8c1 was adapted to the guinea pig by serial passage in the a nimals until secondary lesions were observed. Analysis of the virus directl y recovered from the lesions developed by the animals revealed the selectio n of variants,vith two amino acid substitutions in nonstructural proteins, I-248-->T in 2C and Q(44)-->R in 3A. On further passages, an additional mut ation, L-147-->P, was selected in an important antigenic site located in th e G-H loop of capsid protein VP1. The amino acid substitution Q(44)-->R in 3A, either alone or in combination,vith the replacement I-248-->T in 2C, wa s sufficient to give FMDV the ability to produce lesions. This was shown by using infectious transcripts which generated chimeric viruses,vith the rel evant amino acid substitutions. Clinical symptoms produced by the artificia l chimeras were similar to those produced by the naturally adapted virus. T hese results obtained with FMDV imply that one or very few replacements in nonstructural viral proteins, which should be within reach of the mutant sp ectra of replicating viral quasispecies, may result in adaptation of a viru s to a new animal host.