Deterministic, Compensatory Mutational Events in the Capsid of Foot-and-Mouth Disease Virus in Response to the Introduction of Mutations Found in Viruses from Persistent Infections

Abstract

The evolution of foot-and-mouth disease virus (FMDV) (biological clone C-S8c1) in persistently infected cells led to the emergence of a variant (R100) that displayed increased virulence, reduced stability, and other modified phenotypic traits. Some mutations fixed in the R100 genome involved a cluster of highly conserved residues around the capsid pores that participate in interactions with each other and/or between capsid protomers. We have investigated phenotypic and genotypic changes that occurred when these replacements were introduced into the C-S8c1 capsid. The C3007V and M3014L mutations exerted no effect on plaque size or viral yield during lytic infections, or on virion stability, but led to a reduction in biological fitness; the D3009A mutation caused drastic reductions in plaque size and viability. Remarkably, competition of the C3007V mutant with the nonmutated virus invariably resulted in the fixation of the D3009A mutation in the C3007V capsid. In turn, the presence of the D3009A mutation invariably led to the fixation of the M3014L mutation. In both cases, two individually disadvantageous mutations led, together, to an increase in fitness, as the double mutants outcompeted the nonmutated genotype. The higher fitness of C3007V/D3009A was related to a faster multiplication rate. These observations provide evidence for a chain of linked, compensatory mutational events in a defined region of the FMDV capsid. Furthermore, they indicate that the clustering of unique amino acid replacements in viruses from persistent infections may also occur in cytolytic infections in response to changes caused by previous mutations without an involvement of the new mutations in the adaptation to a different environment.

Coordinated evolution of the hepatitis C virus

“…A large number of mutations in tightly organized RNA viral genomes should lead to frequent epistatic interactions between sites. Several experiments have provided strong evidence of extensive epistasis in RNA viruses, confirming that during viral evolution certain substitutions at different sites may occur in a coordinated manner (7)(8)(9)(10)(11)(12). Experimental studies into the adaptation of genetically modified HCV genomes propagated in cell culture also have shown antagonistic epistatic interactions between deleterious mutations exhibited in the form of compensatory mutations (13)(14)(15).…”

Rescue of Deleterious Mutations by the Compensatory Y30F Mutation in Ketosteroid Isomerase

“…1. Spatially close compensatory mutations were also observed in the foot-and-mouth disease virus capsid and in the DNA bacteriophage ΦX174 (Mateo and Mateu, 2007;Poon and Chao, 2005). Analysis of compensatory mutation frequency in DNA bacteriophage ΦX174 revealed that many compensatory mutations occur at spatially close residues (Poon and Chao, 2005).…”

Mapping of antigenic determinants on a SAT2 foot-and-mouth disease virus using chicken single-chain antibody fragments

“…Therefore, it is unlikely that soluble scFv2 is directed to internally located residues and T4→S was discarded as a possible antigenic site. The T4→S residue change could be accounted for either as a result of a compensatory mutational event due to possible structural rearrangements following a distant effect (Grazioli et al, 2006;Mateo and Mateu, 2007) or due to the quasispecies nature of FMDV. Since the majority of virus escape mutants involve the interaction of a surfaceorientated side-chain with a MAb, the surface exposed residue change R159→H in VP1, located at the C-terminal base of the G-H loop, was thought to be involved in binding of the soluble scFv2.…”