New research published in the Journal of Clinical Investigation challenges a widely held opinion that poliovirus tropism for the brain, spinal cord and other tissues, and attenuation of the Sabin vaccine strain are mediated at the level of viral RNA translation.

Previous work has shown that poliovirus tropism and pathogenesis are determined by events that occur after the virus has entered a cell and that the cell-type-specific differences observed are linked to the virus internal ribosome entry site (IRES; a noncoding genomic element that allows the internal binding of ribosomes in a 5′ end and cap-independent manner). Indeed, analysis of attenuated and neurovirulent polioviruses has provided substantial evidence for the role of the IRES in poliovirus biology, leading to the interpretation that alterations in the IRES reduces viral RNA translation in attenuated poliovirus strains, and in host cells that are not neuronal in origin. In their study, Steven Kauder and Vincent Racaniello set out to formally test this hypothesis. Using bicistronic reporter genes, the authors were able to demonstrate that poliovirus IRES-dependent translation occurred in many organs, including those that do not normally support poliovirus replication. The authors were further able to show that in a transgenic mouse model of poliomyelitis, poliovirus containing the substituted IRES retained the wild-type tropism for the brain and spinal cord. Replication was also observed in these tissues even after the introduction of a single point mutation (C472U) into the IRES, which is a mutation thought to be an important determinant of poliovirus attenuation of neurovirulence. Interestingly, in polioviruses with this mutation, neurovirulence and paralysis were only observed in newborn mice.

In combination, these results clearly demonstrate that the tropism of wild-type and vaccine strains of poliovirus do not operate primarily at the level of IRES-mediated translation initiation but at a later, post-tanslational, stage of the intracellular virus life cycle. These conclusions differ from those derived from previous in vitro and ex vivo analyses which, as the authors point out, reinforce the concept that the ultimate outcome of any viral infection is the result of a complex interplay between virus and host.