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Journal of Virology, December 2006, p. 11579-11588, Vol. 80, No. 23
0022-538X/06/$08.00+0     doi:10.1128/JVI.00675-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The Hepatitis C Virus RNA 3'-Untranslated Region Strongly Enhances Translation Directed by the Internal Ribosome Entry Site{triangledown}

Yutong Song,1 Peter Friebe,2 Eleni Tzima,1 Christiane Jünemann,1 Ralf Bartenschlager,2 and Michael Niepmann1*

Institute of Biochemistry, Faculty of Medicine, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany,1 Department of Molecular Virology, Faculty of Medicine, University of Heidelberg, Heidelberg, Germany2

Received 4 April 2006/ Accepted 2 September 2006

The positive-strand RNA genome of the hepatitis C virus (HCV) is flanked by 5'- and 3'-untranslated regions (UTRs). Translation of the viral RNA is directed by the internal ribosome entry site (IRES) in the 5'-UTR, and subsequent viral RNA replication requires sequences in the 3'-UTR and in the 5'-UTR. Addressing previous conflicting reports on a possible function of the 3'-UTR for RNA translation in this study, we found that reporter construct design is an important parameter in experiments testing 3'-UTR function. A translation enhancer function of the HCV 3'-UTR was detected only after transfection of monocistronic reporter RNAs or complete RNA genomes having a 3'-UTR with a precise 3' terminus. The 3'-UTR strongly stimulates HCV IRES-dependent translation in human hepatoma cell lines but only weakly in nonliver cell lines. The variable region, the poly(U · C) tract, and the most 3' terminal stem-loop 1 of the highly conserved 3' X region contribute significantly to translation enhancement, whereas stem-loops 2 and 3 of the 3' X region are involved only to a minor extent. Thus, the signals for translation enhancement and for the initiation of RNA minus-strand synthesis in the HCV 3'-UTR partially overlap, supporting the idea that these sequences along with viral and possibly also cellular factors may be involved in an RNA 3'-5' end interaction and a switch between translation and RNA replication.

* Corresponding author. Mailing address: Institute of Biochemistry, Faculty of Medicine, Justus-Liebig-University Giessen, Friedrichstrasse 24, 35392 Giessen, Germany. Phone: 49 641 99 47471. Fax: 49 641 99 47429. E-mail: michael.niepmann{at}biochemie.med.uni-giessen.de.

{triangledown} Published ahead of print on 13 September 2006.

Journal of Virology, December 2006, p. 11579-11588, Vol. 80, No. 23
0022-538X/06/$08.00+0     doi:10.1128/JVI.00675-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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