Key result
V-073-resistant poliovirus variants were on average 1.4 log10 less neurovirulent than drug-susceptible parental viruses while maintaining immunological features.
Why the study?
Do V-073-resistant poliovirus variants maintain immunological features and exhibit altered pathogenic properties compared to susceptible viruses?
Do V-073-resistant poliovirus variants maintain immunological features and exhibit altered pathogenic properties compared to susceptible viruses?
Laboratory-derived V-073-resistant poliovirus variants exhibit attenuated neurovirulence while maintaining the immunological features of drug-susceptible viruses.
Supports V-073 development for polio; animal data leave open human translation of attenuated neurovirulence.
BACKGROUND: The National Research Council has recommended development of polio antiviral drugs to assist in management of outbreaks and to mitigate adverse consequences of vaccination. V-073 is a small molecule poliovirus capsid inhibitor that is being developed for these purposes. Antiviral use raises the potential of treatment-emergent resistance. Understanding virological consequences of resistance is important. METHODS: Six independent laboratory-derived V-073-resistant poliovirus variants were characterized for their ability to be neutralized by conventional vaccine-induced immune sera, to elicit serum neutralizing antibodies upon CD-1 mouse immunization, and to replicate in and to cause paralysis of TgPVR21 mice. RESULTS: V-073-resistant variants were effectively neutralized by oral poliovirus vaccine and inactivated poliovirus vaccine human immune sera. All variants elicited virus neutralizing antibody titres in CD-1 mice that were comparable to drug-susceptible parental and Sabin vaccine strain viruses. Infection efficiency of TgPVR21 mice by variants was comparable to (1 of 6 variants) or considerably lower than (5 of 6 variants) parental viruses. Drug-resistant variants replicated to levels comparable to (1 of 6 variants) or substantially less than (5 of 6 variants) their drug-susceptible parental viruses and were on average 1.4 log(10) (range 0.3 to >2.8 log₁₀) less neurovirulent. CONCLUSIONS: Laboratory-derived V-073-resistant variants exhibit clear attenuation of pathogenic properties while maintaining immunological features of drug-susceptible viruses.
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Kouiavskaia et al. (2011) studied Poliovirus infection. V-073-resistant poliovirus variants vs. Drug-susceptible parental and Sabin vaccine strain viruses was evaluated on Neurovirulence and replication in TgPVR21 mice. V-073-resistant poliovirus variants were on average 1.4 log10 less neurovirulent than drug-susceptible parental viruses while maintaining immunological features.
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