Functional long-range RNA–RNA interactions in positive-strand RNA viruses

Long-range RNA–RNA interactions, many of which span several thousands of nucleotides, have been discovered within the genomes of positive-strand RNA viruses. These interactions mediate fundamental viral processes, including translation, replication and transcription.In certain plant viruses that have uncapped, non-polyadenylated RNA genomes, translation initiation is facilitated by 3′ cap-independent translational enhancers (3′ CITEs) that are located in or near to their 3′ UTRs. These RNA elements function by binding to either the ribosome-recruiting eukaryotic translation initiation factor 4F (eIF4F) complex or ribosomal subunits, and they enhance translation initiation by engaging the 5′ end of the genome via a 5′-to-3′ RNA-based bridge.The activities of the internal ribosome entry sites (IRESs) in the 5′ UTRs of various viruses are modulated by RNA-based interactions between the IRESs and elements near to the 3′ ends of their genomes.In several plant viruses, translational recoding events, including ribosomal frameshifting and stop codon readthrough, have been found to rely on long-range RNA–RNA interactions.Multiple 5′-to-3′ base-pairing interactions facilitate genome circularization in flaviviruses, which has been proposed to reposition the 5′-bound RNA-dependent RNA polymerase (RdRp) to the initiation site of negative-strand synthesis at the 3′ terminus.The long-distance interaction between two cis-acting replication elements in tombusviruses generates a bipartite RNA platform for the assembly of the replicase complex and repositions the internally bound RdRp to the 3′ terminus.Tombusviruses also rely on several long-range interactions that mediate the premature termination of the RdRp during negative-strand synthesis that leads to transcription of subgenomic mRNAs (sgmRNAs).In a coronavirus, an exceptionally long-range interaction, which spans ∼26,000 nucleotides, promotes polymerase repriming during the discontinuous template synthesis step of sgmRNA-N transcription.A challenge for the future will be to determine how these long-range interactions are integrated and regulated in the complex context of viral RNA genomes.