Structure-function relationship in viral RNA genomes: The case of hepatitis C virus

Abstract

The acquisition of a storage information system beyond the nucleotide sequence has been a crucial issue for the propagation and dispersion of RNA viruses. This system is composed by highly conserved, complex structural units in the genomic RNA, termed functional RNA domains. These elements interact with other regions of the viral genome and/or proteins to direct viral translation, replication and encapsidation. The genomic RNA of the hepatitis C virus (HCV) is a good model for investigating about conserved structural units. It contains functional domains, defined by highly conserved structural RNA motifs, mostly located in the 5’-untranslatable regions (5’UTRs) and 3’UTR, but also occupying long stretches of the coding sequence. Viral translation initiation is mediated by an internal ribosome entry site located at the 5’ terminus of the viral genome and regulated by distal functional RNA domains placed at the 3’ end. Subsequent RNA replication strongly depends on the 3’UTR folding and is also influenced by the 5’ end of the HCV RNA. Further increase in the genome copy number unleashes the formation of homodimers by direct interaction of two genomic RNA molecules, which are finally packed and released to the extracellular medium. All these processes, as well as transitions between them, are controlled by structural RNA elements that establish a complex, direct and long-distance RNA-RNA interaction network. This review summarizes current knowledge about functional RNA domains within the HCV RNA genome and provides an overview of the control exerted by direct, long-range RNA-RNA contacts for the execution of the viral cycle.

Keywords: Functional RNA domain, Cis-acting replicating element, Hepatitis C virus, Internal ribosome entry site, RNA-RNA interaction, Untranslatable region

Core tip: This review summarizes the main aspects of structurally conserved genomic RNA elements in the hepatitis C virus (HCV) genome and their role in the viral cycle. The genome of RNA viruses is a dynamic genetic entity endorsed with an information storage system defined by highly conserved, complex structural units, termed functional RNA domains. The genome of HCV contains several well-studied functional RNA domains that control essential viral processes, as well as transitions between them, by recruiting protein factors and also by establishing a complex, direct and long-range RNA-RNA interaction network.