Hepatitis C virus genomic RNA dimerization is mediated via a kissing complex intermediate
- 1 April 2010
- journal article
- Published by Cold Spring Harbor Laboratory in RNA
- Vol. 16 (5), 913-925
- https://doi.org/10.1261/rna.1960410
Abstract
With over 200 million people infected with hepatitis C virus (HCV) worldwide, there is a need for more effective and better-tolerated therapeutic strategies. The HCV genome is a positive-sense; single-stranded RNA encoding a large polyprotein cleaved at multiple sites to produce at least ten proteins, among them an error-prone RNA polymerase that confers a high mutation rate. Despite considerable overall sequence diversity, in the 3′-untranslated region of the HCV genomic RNA there is a 98-nucleotide (nt) sequence named X RNA, the first 55 nt of which (X55 RNA) are 100% conserved among all HCV strains. The X55 region has been suggested to be responsible for in vitro dimerization of the genomic RNA in the presence of the viral core protein, although the mechanism by which this occurs is unknown. In this study, we analyzed the X55 region and characterized the mechanism by which it mediates HCV genomic RNA dimerization. Similar to a mechanism proposed previously for the human immunodeficiency 1 virus (HIV-1) genome, we show that dimerization of the HCV genome involves formation of a kissing complex intermediate, which is converted to a more stable extended duplex conformation in the presence of the core protein. Mutations in the dimer linkage sequence loop sequence that prevent RNA dimerization in vitro significantly reduced but did not completely ablate the ability of HCV RNA to replicate or produce infectious virus in transfected cells.Keywords
This publication has 50 references indexed in Scilit:
- Hepatitis C: recent successes and continuing challenges in the development of improved treatment modalitiesCurrent Opinion in Pharmacology, 2009
- HIV-1 Nucleocapsid Protein Switches the Pathway of Transactivation Response Element RNA/DNA Annealing from Loop–Loop “Kissing” to “Zipper”Journal of Molecular Biology, 2009
- A Dynamic View of Hepatitis C Virus Replication ComplexesJournal of Virology, 2008
- RNA chaperoning and intrinsic disorder in the core proteins of FlaviviridaeNucleic Acids Research, 2007
- Synthesis of HIV-1 Ψ-site RNA sequences with site specific incorporation of the fluorescent base analog 2-aminopurineTetrahedron, 2007
- Nucleocapsid protein-mediated maturation of dimer initiation complex of full-length SL1 stemloop of HIV-1: sequence effects and mechanism of RNA refoldingNucleic Acids Research, 2007
- The Hepatitis C Virus RNA 3′-Untranslated Region Strongly Enhances Translation Directed by the Internal Ribosome Entry SiteJournal of Virology, 2006
- Analysis of hepatitis C virus RNA dimerization and core-RNA interactionsNucleic Acids Research, 2006
- Structural biology of hepatitis C virusHepatology, 2004
- Genetic Analysis of Internal Ribosomal Entry Site on Hepatitis C Virus RNA: Implication for Involvement of the Highly Ordered Structure and Cell Type-Specific Transacting FactorsVirology, 1997