Long polycytidine (polyC) tracts varying in length from 50 to 400 nucleotides were first described in the 5′-noncoding region (NCR) of genomes of picornaviruses belonging to the Cardio- and Aphthovirus genera over 50 years ago, but the molecular basis of their function is still unknown. Truncation or complete deletion of the polyC tracts in picornaviruses compromises virulence and pathogenicity but do not affect replicative fitness in vitro, suggesting a role as “viral security” RNA element. The evidence available suggests that the presence of a long polyC tract is required for replication in immune cells, which impacts viral distribution and targeting, and, consequently, pathogenic progression. Viral attenuation achieved by reduction of the polyC tract length has been successfully used for vaccine strategies. Further elucidation of the role of the polyC tract in viral replication cycle and its connection with replication in immune cells has the potential to expand the arsenal of tools in the fight against cancer in oncolytic virotherapy (OV). Here, we review the published data on the biological significance and mechanisms of action of the polyC tract in viral pathogenesis in Cardio- and Aphthoviruses.

Virus-infected cells release type 1 interferons, which induce an antiviral state in neighboring cells. Naturally occurring viruses are therefore equipped with stealth replication strategies to limit virus sensing and/or with combat strategies to prevent or reverse the antiviral state. Here we show that oncolytic viruses with simple RNA genomes whose spread was suppressed in tumor cells pretreated with interferon were able to replicate efficiently when the cells were coinfected with a poxvirus known to encode a diversity of innate immune combat proteins. In vivo the poxvirus was shown to reverse the intratumoral antiviral state, rescuing RNA virus replication in an otherwise restrictive syngeneic mouse tumor model leading to antitumor efficacy. Pairing of complementary oncolytic viruses is a promising strategy to enhance the antitumor activity of this novel class of anticancer drugs.

No abstract