Many hopes have been placed on ribozymes as agents for fighting viral diseases, especially those caused by RNA viruses. The principle underlying the use of these molecules is their recognition of specific target RNA sequences, and the subsequent cleavage of these by the ribozyme catalytic domain. These events have been extensively documented through the use of in vitro models. However, a number of obstacles have limited the clinical value of ribozymes. An important one is that ribozymes have to compete with the natural folding of the viral RNA target molecules if they are to efficiently access their cognate substrate sequence motif. This chapter provides evidence that ribozymes can, however, be optimized through the addition of an RNA element that promotes their efficient binding to specific structural domains within the target RNA. Ribozyme access to the cleavable phosphodiester bond is thus facilitated, rendering antiviral activity more efficient.

The genus Flavivirus comprises numerous, small, single positive-stranded RNA viruses, many of which are important human pathogens. To store all the information required for their successful propagation, flaviviruses use discrete structural genomic RNA elements to code for functional information by the establishment of dynamic networks of long-range RNA–RNA interactions that promote specific folding. These structural elements behave as true cis-acting, non-coding RNAs (ncRNAs) and have essential regulatory roles in the viral cycle. These include the control of the formation of subgenomic RNAs, known as sfRNAs, via the prevention of the complete degradation of the RNA genome. These sfRNAs are important in ensuring viral fitness. This work summarizes our current knowledge of the functions performed by the genome conformations and the role of RNA–RNA interactions in these functions. It also reviews the role of RNA structure in the production of sfRNAs across the genus Flavivirus, and their existence in related viruses.

RNA virus genomes are multifunctional entities endowed with conserved structural elements that control translation, replication and encapsidation, among other processes. The preservation of these structural RNA elements constraints the genomic sequence variability. The hepatitis C virus (HCV) genome is a positive, single-stranded RNA molecule with numerous conserved structural elements that manage different steps during the infection cycle. Their function is ensured by the association of protein factors, but also by the establishment of complex, active, long-range RNA-RNA interaction networks-the so-called HCV RNA interactome. This review describes the RNA genome functions mediated via RNA-RNA contacts, and revisits some canonical ideas regarding the role of functional high-order structures during the HCV infective cycle. By outlining the roles of long-range RNA-RNA interactions from translation to virion budding, and the functional domains involved, this work provides an overview of the HCV genome as a dynamic device that manages the course of viral infection.