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

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 pote...

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Bibliographic Details
Published in:Antiviral therapy 2011-10, Vol.16 (7), p.999-1004
Main Authors: KOUIAVSKAIA, Diana V, DRAGUNSKY, Eugenia M, LIU, Hong-Mei, OBERSTE, M. Steven, COLLETT, Marc S, CHUMAKOV, Konstantin M
Format: Article
Language:English
Subjects:
Animals
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antibodies, Neutralizing - biosynthesis
Antibodies, Neutralizing - immunology
Antibodies, Viral - biosynthesis
Antibodies, Viral - immunology
Antigens, Viral - immunology
Antiviral agents
Antiviral Agents - pharmacology
Biological and medical sciences
Capsid Proteins - antagonists & inhibitors
Cell Line
Drug Resistance, Viral
Female
Humans
Male
Medical sciences
Mice
Mice, Transgenic
Neutralization Tests
Pharmacology. Drug treatments
Poliomyelitis - drug therapy
Poliomyelitis - immunology
Poliomyelitis - virology
Poliovirus - drug effects
Poliovirus - genetics
Poliovirus - immunology
Poliovirus - pathogenicity
Poliovirus Vaccine, Inactivated - immunology
Poliovirus Vaccine, Oral - immunology
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Summary: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. 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. 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. Laboratory-derived V-073-resistant variants exhibit clear attenuation of pathogenic properties while maintaining immunological features of drug-susceptible viruses.
ISSN:1359-6535
2040-2058
DOI:10.3851/imp1838