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Open AccessArticle

Genomic-Scale Interaction Involving Complementary Sequences in the Hepatitis C Virus 5′UTR Domain IIa and the RNA-Dependent RNA Polymerase Coding Region Promotes Efficient Virus Replication

1
Laboratory of viral pathogenesis, Research Center, CHU Sainte-Justine, 3175 Côte Sainte-Catherine Road, Montréal, Québec H3T 1C5, Canada
2
Département de microbiologie, infectiologie, immunologie, Université de Montréal, Québec, H3T 1C5, Canada
*
Author to whom correspondence should be addressed.
Viruses 2019, 11(1), 17; https://doi.org/10.3390/v11010017
Received: 14 November 2018 / Revised: 22 December 2018 / Accepted: 23 December 2018 / Published: 28 December 2018
(This article belongs to the Special Issue CSV2018: The 2nd symposium of the Canadian Society for Virology (CSV))
The hepatitis C virus (HCV) genome contains structured elements thought to play important regulatory roles in viral RNA translation and replication processes. We used in vitro RNA binding assays to map interactions involving the HCV 5′UTR and distal sequences in NS5B to examine their impact on viral RNA replication. The data revealed that 5′UTR nucleotides (nt) 95–110 in the internal ribosome entry site (IRES) domain IIa and matching nt sequence 8528–8543 located in the RNA-dependent RNA polymerase coding region NS5B, form a high-affinity RNA-RNA complex in vitro. This duplex is composed of both wobble and Watson-Crick base-pairings, with the latter shown to be essential to the formation of the high-affinity duplex. HCV genomic RNA constructs containing mutations in domain IIa nt 95–110 or within the genomic RNA location comprising nt 8528–8543 displayed, on average, 5-fold less intracellular HCV RNA and 6-fold less infectious progeny virus. HCV genomic constructs containing complementary mutations for IRES domain IIa nt 95–110 and NS5B nt 8528–8543 restored intracellular HCV RNA and progeny virus titers to levels obtained for parental virus RNA. We conclude that this long-range duplex interaction between the IRES domain IIa and NS5B nt 8528–8543 is essential for optimal virus replication. View Full-Text
Keywords: NS5B; secondary structure; circular RNA; RNA folding; RNA stem-loop; HCV IRES; long-distance RNA–RNA interaction; Flaviviridae NS5B; secondary structure; circular RNA; RNA folding; RNA stem-loop; HCV IRES; long-distance RNA–RNA interaction; Flaviviridae
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Rance, E.; Tanner, J.E.; Alfieri, C. Genomic-Scale Interaction Involving Complementary Sequences in the Hepatitis C Virus 5′UTR Domain IIa and the RNA-Dependent RNA Polymerase Coding Region Promotes Efficient Virus Replication. Viruses 2019, 11, 17.

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