Mode of selection and experimental evolution of antiviral drugs resistance in vesicular stomatitis virus

The possession of an antiviral resistance mutation benefits a virus when the corresponding antiviral is present. But does the resistant virus pay a fitness cost when the antiviral is absent? Would an evolutionary history of association between a genotype and a resistance mutation overcome this cost by changes compensating the harmful side-effect of resistance mutations? Are combined therapies more effective against the rise of resistant viruses or against evolutionary compensations? To explore all these questions, we took an experimental evolution approach. After selecting vesicular stomatitis virus (VSV) populations able to replicate under increasing concentrations of ribavirin and/or alpha-interferon, we evolved them for more than 100 generations under sub-inhibitory concentrations of the corresponding antivirals, allowing for evolutionary compensation. Our results show that resistance for these two antivirals was not easily achieved, being the selected populations generally less fit than the ancestrals both in presence and absence of the antivirals. Evolution in presence of sub-inhibitory concentrations of antivirals compensated for the reduction in fitness in presence of antiviral therapy.