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Journal of Virology, May 2001, p. 4614-4624, Vol. 75, No. 10
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.10.4614-4624.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Enhancement of Hepatitis C Virus RNA Replication by Cell Culture-Adaptive Mutations

Nicole Krieger, Volker Lohmann, and Ralf Bartenschlager*

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

Received 21 December 2000/Accepted 21 February 2001

Studies of the Hepatitis C virus (HCV) replication cycle have been made possible with the development of subgenomic selectable RNAs that replicate autonomously in cultured cells. In these replicons the region encoding the HCV structural proteins was replaced by the neomycin phosphotransferase gene, allowing the selection of transfected cells that support high-level replication of these RNAs. Subsequent analyses revealed that, within selected cells, HCV RNAs had acquired adaptive mutations that increased the efficiency of colony formation by an unknown mechanism. Using a panel of replicons that differed in their degrees of cell culture adaptation, in this study we show that adaptive mutations enhance RNA replication. Transient-transfection assays that did not require selection of transfected cells demonstrated a clear correlation between the level of adaptation and RNA replication. The highest replication level was found with an adapted replicon carrying two amino acid substitutions located in NS3 and one in NS5A that acted synergistically. In contrast, the nonadapted RNA replicated only transiently and at a low level. The correlation between the efficiency of colony formation and RNA replication was corroborated with replicons in which the selectable marker gene was replaced by the gene encoding firefly luciferase. Upon transfection of naive Huh-7 cells, the levels of luciferase activity directly reflected the replication efficiencies of the various replicon RNAs. These results show that cell culture-adaptive mutations enhance HCV RNA replication.

* 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, May 2001, p. 4614-4624, Vol. 75, No. 10
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.10.4614-4624.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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