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Foot-and-mouth disease virus (FMDV) is a picornavirus that exhibits an extremely acid sensitive capsid. This acid lability is directly related to its mechanism of uncoating triggered by acidification inside cellular endosomes. Using a collection of FMDV mutants we have systematically analyzed the relationship between acid stability and the requirement for acidic endosomes using ammonium chloride (NH 4 Cl), an inhibitor of endosome acidification. A FMDV mutant carrying two substitutions with opposite effects on acid-stability (VP3 A116V that reduces acid stability, and VP1 N17D that increases acid stability) displayed a rapid shift towards acid lability that resulted in increased resistance to NH 4 Cl as well as to concanamicyn A, a different lysosomotropic agent. This resistance could be explained by a higher ability of the mutant populations to produce NH 4 Cl-resistant variants, as supported by their tendency to accumulate mutations related to NH 4 Cl-resistance that was higher than that of the WT populations. Competition experiments also indicated that the combination of both amino acid substitutions promoted an increase of viral fitness that likely contributed to NH 4 Cl resistance. This study provides novel evidences supporting that the combination of mutations in a viral capsid can result in compensatory effects that lead to fitness gain, and facilitate space to an inhibitor of acid-dependent uncoating. Thus, although drug-resistant variants usually exhibit a reduction in viral fitness, our results indicate that compensatory mutations that restore this reduction in fitness can promote emergence of resistance mutants.

Adaptive value of foot-and-mouth disease virus capsid substitutions with opposite effects on particle acid stability