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Antimicrobial Agents and Chemotherapy, December 2008, p. 4356-4369, Vol. 52, No. 12
0066-4804/08/$08.00+0     doi:10.1128/AAC.00444-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Selected Replicon Variants with Low-Level In Vitro Resistance to the Hepatitis C Virus NS5B Polymerase Inhibitor PSI-6130 Lack Cross-Resistance with R1479 ^,

Samir Ali,¹ Vincent Leveque,¹ Sophie Le Pogam,¹ Han Ma,¹ Friederike Philipp,¹ Nicole Inocencio,¹ Mark Smith,¹ Andre Alker,² Hyunsoon Kang,¹ Isabel Najera,¹ Klaus Klumpp,¹ Julian Symons,¹ Nick Cammack,¹ and Wen-Rong Jiang^1*

Roche Palo Alto LLC, Palo Alto, California,¹ Hoffman-La Roche, Basel, Switzerland²

Received 3 April 2008/ Returned for modification 2 June 2008/ Accepted 26 September 2008

PSI-6130 (β-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine) is a selective inhibitor of hepatitis C virus (HCV) replication that targets the NS5B polymerase. R7128, the prodrug of PSI-6130, has shown antiviral efficacy in patients chronically infected with HCV genotype 1a (GT-1a) and GT-1b. We observed that the compound exhibited potent in vitro activity against laboratory-optimized HCV replicons as well as against a panel of replicons containing NS5B HCV polymerases derived from GT-1a and GT-1b clinical isolates. We used the HCV replicon cell system to examine the emergence of variants with reduced sensitivity to PSI-6130. Short-term treatment of cells harboring the HCV subgenomic replicon with PSI-6130 cleared the replicon without generating resistant variants. Long-term culture of the cells under the compound selection generated the S282T substitution in a complex pattern with other amino acid substitutions in the NS5B polymerase. The presence of the coselected substitutions did not increase the moderate three- to sixfold loss of sensitivity to PSI-6130 mediated by the S282T substitution; however, their presence enhanced the replication capacity compared to the replication levels seen with the S282T substitution alone. We also observed a lack of cross-resistance between PSI-6130 and R1479 and demonstrated that long-term culture selection with PSI-6130 in replicon cells harboring preexisting mutations resistant to R1479 (S96T/N142T) results in the emergence of the S282T substitution and the reversion of S96T to wild-type serine. In conclusion, PSI-6130 presents a high barrier to resistance selection in vitro, selects for variants exhibiting only low-level resistance, and lacks cross-resistance with R1479, supporting the continued development of the prodrug R7128 as a therapeutic agent for the treatment of HCV infection.

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* Corresponding author. Mailing address: Roche Palo Alto LLC, 3431 Hillview Ave., Palo Alto, CA 94304. Phone: (650) 855-5240. Fax: (650) 852-1187. E-mail: wen-rong.jiang{at}roche.com

Published ahead of print on 6 October 2008.

Supplemental material for this article may be found at http://aac.asm.org/.

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Antimicrobial Agents and Chemotherapy, December 2008, p. 4356-4369, Vol. 52, No. 12
0066-4804/08/$08.00+0     doi:10.1128/AAC.00444-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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