MicroRNAs (miRNAs) are a class of small, ~22 nt regulatory RNAs that modulate a diverse array of cellular activities. Through recognition of sequence complementary target elements found most often in the 3′ untranslated region (UTR) of cellular mRNAs, miRNAs post-transcriptionally regulate numerous cellular processes by way of mRNA translation inhibition or, less commonly, by catalytic mRNA degradation. It is thought that upwards of one-third of all human mRNAs are regulated by the over 700 human miRNAs that are currently known. Many miRNAs can have tissue-specific localizations and, in addition, some are now known to have cancer-specific signatures. The mechanisms by which a miRNA regulates a given mRNA are influenced by parameters such as the degree of sequence homology and target site multiplicity as well as by features of the mRNA itself, including target site secondary structure and location. In addition, the cellular machinery used to translate mRNAs is thought to profoundly affect miRNA regulation. While capped mRNAs are known to be amenable to both catalytic miRNA-induced cleavage and miRNA-mediated translational repression, it has been suggested that uncapped mRNAs that rely on an IRES (Internal Ribosome Entry Site) for translation initiation (such as picornavirus genomes) are not susceptible to translational repression.
Virus host range is shaped by cellular determinants such as transcription factors and receptor expression. In addition, tissue-specific microRNAs can be utilized to direct the specificity of a replication competent picornavirus, Coxsackievirus A21. This report demonstrates the mechanism by which microRNAs are able to directly influence oncolytic viruses, an important class of anticancer agents. It show that microRNA expression is an important determinant of permissivity to picornavirus replication, but the actual abundance of that expression is far more important. There are actually multiple different stages in the life cycle of a replication competent picornavirus that are amenable to regulation by cellular microRNAs. microRNAs can regulate virus tropism in vivo, but circulating high virus titers in the blood can overcome this mechanism of conferring tissue specificity. MicroRNAs are well known to have both oncogenic or oncosuppressive activities in human cancers. Tissue-specific microRNA expression can thus be used to modulate the efficacy of viral anticancer therapeutics.
MicroRNA Antagonism of the Picornaviral Life Cycle: Alternative Mechanisms of Interference. 2010 PLoS Pathog 6(3): e1000820. doi:10.1371/journal.ppat.1000820
In addition to modulating the function and stability of cellular mRNAs, microRNAs can profoundly affect the life cycles of viruses bearing sequence complementary targets, a finding recently exploited to ameliorate toxicities of vaccines and oncolytic viruses. To elucidate the mechanisms underlying microRNA-mediated antiviral activity, we modified the 3′ untranslated region (3′UTR) of Coxsackievirus A21 to incorporate targets with varying degrees of homology to endogenous microRNAs. We show that microRNAs can interrupt the picornavirus life-cycle at multiple levels, including catalytic degradation of the viral RNA genome, suppression of cap-independent mRNA translation, and interference with genome encapsidation. In addition, we have examined the extent to which endogenous microRNAs can suppress viral replication in vivo and how viruses can overcome this inhibition by microRNA saturation in mouse cancer models.