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

Key Points

• 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.

Supplementary information

The online version of this article (doi:10.1038/nrmicro3288) contains supplementary material, which is available to authorized users.

Abstract

Long-range intragenomic RNA–RNA interactions in the genomes of positive-strand RNA viruses involve direct nucleotide base pairing and can span distances of thousands of nucleotides. In this Review, Nicholson and White discuss recent insights into the structure and function of these genomic features and highlight their diverse roles in the gene expression and genome replication of positive-strand RNA viruses.

Supplementary information

The online version of this article (doi:10.1038/nrmicro3288) contains supplementary material, which is available to authorized users.

Abstract

Positive-strand RNA viruses are important human, animal and plant pathogens that are defined by their single-stranded positive-sense RNA genomes. In recent years, it has become increasingly evident that interactions that occur between distantly positioned RNA sequences within these genomes can mediate important viral activities. These long-range intragenomic RNA–RNA interactions involve direct nucleotide base pairing and can span distances of thousands of nucleotides. In this Review, we discuss recent insights into the structure and function of these intriguing genomic features and highlight their diverse roles in the gene expression and genome replication of positive-strand RNA viruses.

Supplementary information

The online version of this article (doi:10.1038/nrmicro3288) contains supplementary material, which is available to authorized users.