Immunological and pathogenic properties of poliovirus variants selected for resistance to antiviral drug V-073.
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.
Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, MD, USA.
Diana V
DV
Kouiavskaia
Eugenia M
EM
Dragunsky
Hong-Mei
HM
Liu
M Steven
MS
Oberste
Marc S
MS
Collett
Konstantin M
KM
Chumakov
D000818:Animals; D057134:Antibodies, Neutralizing / Q000096:biosynthesis / Q000276:immunology; D000914:Antibodies, Viral / Q000096:biosynthesis / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology; D000998:Antiviral Agents / Q000494:pharmacology*; D036022:Capsid Proteins / Q000037:antagonists & inhibitors; D002460:Cell Line; D024882:Drug Resistance, Viral; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009500:Neutralization Tests; D011051:Poliomyelitis / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D017955:Poliovirus / Q000187:drug effects / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity; D011054:Poliovirus Vaccine, Inactivated / Q000276:immunology*; D011055:Poliovirus Vaccine, Oral / Q000276:immunology*
D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000956:Antigens, Viral; D000998:Antiviral Agents; D036022:Capsid Proteins; D011054:Poliovirus Vaccine, Inactivated; D011055:Poliovirus Vaccine, Oral