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Original article

Immunological and pathogenic properties of poliovirus variants selected for resistance to antiviral drug V-073

Diana V Kouiavskaia, Eugenia M Dragunsky, Hong-Mei Liu, M Steven Oberste, Marc S Collett, Konstantin M Chumakov

Corresponding author name: Marc S Collett
Corresponding author e-mail: mscollett@aol.com

Citation: Antiviral Therapy 2011; 16:999-1004
doi: 10.3851/IMP1838

Date accepted: 11 February 2011
Date published online: 30 June 2011

Abstract

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 inactivatedpoliovirus 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 log10 (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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