Abstract
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 (NH4Cl), 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 NH4Cl 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 NH4Cl-resistant variants, as supported by their tendency to accumulate mutations related to NH4Cl-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 NH4Cl 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.
Highlights
Foot-and-mouth disease virus (FMDV) is a picornavirus that exhibits an extremely acid sensitive capsid
Double FMDV mutant VP3 A116V + VP1 N17D does not conform to the canonical relationship between uncoating pH and resistance to NH4Cl
The results suggest the rapid generation of NH4Cl resistant-variants in FMDV VP3 A116V + VP1 N17D populations, a feature not observed for guanidinium hydrochloride (GuHCl) resistant-variants
Summary
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. Capsid proteins are under continuous evolution leading, among others, to extensive antigenic variation, generation of drug-resistant mutants or adaptation to unfavorable environmental conditions. This evolutionary potential is constrained by the need for a balance between functionality and stability because capsids have to be stable enough to protect the genetic material while permitting its release within target host cells. Mutations affecting capsid stability have provided evidence for multifunctional residues[18], the existence of additive e ffects[13,18,29], or the accommodation of compensatory mutations to restore viral fitness[25,30,31], supporting that the stability of FMDV capsid is a multifactorial trait due to the interaction between residues from different capsid p roteins[13]
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