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Journal of Virology, January 2005, p. 380-392, Vol. 79, No. 1
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.1.380-392.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Kissing-Loop Interaction in the 3' End of the Hepatitis C Virus Genome Essential for RNA Replication

Peter Friebe,1 Julien Boudet,2 Jean-Pierre Simorre,2 and Ralf Bartenschlager1*

Department of Molecular Virology, University of Heidelberg, Heidelberg, Germany,1 Institut de Biologie Structurale Jean-Pierre Ebel, Grenoble, France2

Received 7 June 2004/ Accepted 9 August 2004

The hepatitis C virus (HCV) is a positive-strand RNA virus belonging to the Flaviviridae. Its genome carries at either end highly conserved nontranslated regions (NTRs) containing cis-acting RNA elements that are crucial for replication. In this study, we identified a novel RNA element within the NS5B coding sequence that is indispensable for replication. By using secondary structure prediction and nuclear magnetic resonance spectroscopy, we found that this RNA element, designated 5BSL3.2 by analogy to a recent report (S. You, D. D. Stump, A. D. Branch, and C. M. Rice, J. Virol. 78:1352-1366, 2004), consists of an 8-bp lower and a 6-bp upper stem, an 8-nucleotide-long bulge, and a 12-nucleotide-long upper loop. Mutational disruption of 5BSL3.2 structure blocked RNA replication, which could be restored when an intact copy of this RNA element was inserted into the 3' NTR. By using this replicon design, we mapped the elements in 5BSL3.2 that are critical for RNA replication. Most importantly, we discovered a nucleotide sequence complementarity between the upper loop of this RNA element and the loop region of stem-loop 2 in the 3' NTR. Mismatches introduced into the loops inhibited RNA replication, which could be rescued when complementarity was restored. These data provide strong evidence for a pseudoknot structure at the 3' end of the HCV genome that is essential for replication.

* Corresponding author. Mailing address: Department of Molecular Biology, University of Heidelberg, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany. Phone: 49 6221 564569. Fax: 49 6221 564570. E-mail: Ralf_Bartenschlager{at}med.uni-heidelberg.de.

Journal of Virology, January 2005, p. 380-392, Vol. 79, No. 1
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.1.380-392.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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