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Journal of Virology, December 2001, p. 12047-12057, Vol. 75, No. 24
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.24.12047-12057.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Sequences in the 5' Nontranslated Region of Hepatitis C Virus Required for RNA Replication

Peter Friebe, Volker Lohmann, Nicole Krieger, and Ralf Bartenschlager*

Institute for Virology, Johannes-Gutenberg University Mainz, 55131 Mainz, Germany

Received 3 May 2001/Accepted 18 September 2001

Sequences in the 5' and 3' termini of plus-strand RNA viruses harbor cis-acting elements important for efficient translation and replication. In case of the hepatitis C virus (HCV), a plus-strand RNA virus of the family Flaviviridae, a 341-nucleotide-long nontranslated region (NTR) is located at the 5' end of the genome. This sequence contains an internal ribosome entry site (IRES) that is located downstream of an about 40-nucleotide-long sequence of unknown function. By using our recently developed HCV replicon system, we mapped and characterized the sequences in the 5' NTR required for RNA replication. We show that deletions introduced into the 5' terminal 40 nucleotides abolished RNA replication but only moderately affected translation. By generating a series of replicons with HCV-poliovirus (PV) chimeric 5' NTRs, we could show that the first 125 nucleotides of the HCV genome are essential and sufficient for RNA replication. However, the efficiency could be tremendously increased upon the addition of the complete HCV 5' NTR. These data show that (i) sequences upstream of the HCV IRES are essential for RNA replication, (ii) the first 125 nucleotides of the HCV 5' NTR are sufficient for RNA replication, but such replicon molecules are severely impaired for multiplication, and (iii) high-level HCV replication requires sequences located within the IRES. These data provide the first identification of signals in the 5' NTR of HCV RNA essential for replication of this virus.

* Corresponding author. Mailing address: Institute for Virology, Johannes-Gutenberg University Mainz, Obere Zahlbacher Strasse 67, 55131 Mainz, Germany. Phone: 49 6131 393 4451. Fax: 49 6131 393 5604. E-mail: bartnsch{at}mail.uni-mainz.de.

Journal of Virology, December 2001, p. 12047-12057, Vol. 75, No. 24
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.24.12047-12057.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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