Coding Changes in the Poliovirus Protease 2A Compensate for 5′NCR Domain V Disruptions in a Cell-Specific Manner

Polioviruses are single-stranded RNA viruses with an unusually long noncoding region (NCR) at the 5′ end predicted to have an elaborate secondary structure made up of six domains. Mutations in domain V of the poliovirus 5′NCR that disrupt secondary structure are responsible for attenuation of the virus and a temperature-sensitive (ts) phenotype in vitro. In addition to direct back mutation or compensatory second site mutation in the 5′NCR as previously documented, the ts phenotype was found to be compensated for in monkey kidney cells in vitro by a coding change in the protease 2A. These coding changes were found throughout the protease with no obvious pattern or trend. They were not all found to be equivalent and limited in ability to compensate for the severest domain V disruption. The compensatory effect of the 2A changes was found to be cell specific, having no effect on monkey neurovirulence and in a mouse cell line but a significant effect in two monkey cell lines and a human epithelial line.