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Journal of Virology, February 2001, p. 1437-1449, Vol. 75, No. 3
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.3.1437-1449.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Mutations in Hepatitis C Virus RNAs Conferring Cell Culture Adaptation

Volker Lohmann, Frank Körner,dagger Aneta Dobierzewska,Dagger and Ralf Bartenschlager*

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

Received 28 July 2000/Accepted 27 October 2000

As an initial approach to studying the molecular replication mechanisms of hepatitis C virus (HCV), a major causative agent of acute and chronic liver disease, we have recently developed selectable self-replicating RNAs. These replicons lacked the region encoding the structural proteins and instead carried the gene encoding the neomycin phosphotransferase. Although the replication levels of these RNAs within selected cells were high, the number of G418-resistant colonies was reproducibly low. In a search for the reason, we performed a detailed analysis of replicating HCV RNAs and identified several adaptive mutations enhancing the efficiency of colony formation by several orders of magnitude. Adaptive mutations were found in nearly every nonstructural protein but not in the 5' or 3' nontranslated regions. The most drastic effect was found with a single-amino-acid substitution in NS5B, increasing the number of colonies ~500-fold. This mutation was conserved with RNAs isolated from one cell line, in contrast to other amino acid substitutions enhancing the efficiency of colony formation to a much lesser extent. Interestingly, some combinations of these nonconserved mutations with the highly adaptive one reduced the efficiency of colony formation drastically, suggesting that some adaptive mutations are not compatible.

* 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.

dagger Present address: Hoffmann-La Roche AG, 79630 Grenzach-Wyhlen, Germany.

Dagger Present address: Nikolaus Fiebiger Center for Molecular Medicine, University of Erlangen, 91054 Erlangen, Germany.

Journal of Virology, February 2001, p. 1437-1449, Vol. 75, No. 3
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.3.1437-1449.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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