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Antimicrobial Agents and Chemotherapy, October 2005, p. 4305-4314, Vol. 49, No. 10
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.10.4305-4314.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Mutations Conferring Resistance to a Hepatitis C Virus (HCV) RNA-Dependent RNA Polymerase Inhibitor Alone or in Combination with an HCV Serine Protease Inhibitor In Vitro

Hongmei Mo,1* Liangjun Lu,1 Tami Pilot-Matias,1 Ron Pithawalla,1 Rubina Mondal,1 Sherie Masse,1 Tatyana Dekhtyar,1 Teresa Ng,1 Gennadiy Koev,1 Vincent Stoll,2 Kent D. Stewart,2 John Pratt,1 Pam Donner,1 Todd Rockway,1 Clarence Maring,1 and Akhteruzzaman Molla1

Antiviral Research,1 Structural Biology, Abbott Laboratories Global Pharmaceutical Research and Development, Abbott Park, Illinois2

Received 1 February 2005/ Returned for modification 7 April 2005/ Accepted 15 June 2005

Compounds A-782759 (an N-1-aza-4-hydroxyquinolone benzothiadiazine) and BILN-2061 are specific anti-hepatitis C virus (HCV) agents that inhibit the RNA-dependent RNA polymerase and the NS3 serine protease, respectively. Both compounds display potent activity against HCV replicons in tissue culture. In order to characterize the development of resistance to these anti-HCV agents, HCV subgenomic 1b-N replicon cells were cultured with A-782759 alone or in combination with BILN-2061 at concentrations 10 times above their corresponding 50% inhibitory concentrations in the presence of neomycin. Single substitutions in the NS5B polymerase gene (H95Q, N411S, M414L, M414T, or Y448H) resulted in substantial decreases in susceptibility to A-782759. Similarly, replicons containing mutations in the NS5B polymerase gene (M414L or M414T), together with single mutations in the NS3 protease gene (A156V or D168V), conferred high levels of resistance to both A-782759 and BILN-2061. However, the A-782759-resistant mutants remained susceptible to nucleoside and two other classes of nonnucleoside NS5B polymerase inhibitors, as well as interferon. In addition, we found that the frequency of replicons resistant to both compounds was significantly lower than the frequency of resistance to the single compound. Furthermore, the dually resistant mutants displayed significantly reduced replication capacities compared to the wild-type replicon. These findings provide strategic guidance for the future treatment of HCV infection.

* Corresponding author. Mailing address: Department R-47D, Building AP52-N, 200 Abbott Park Road, Abbott Park, IL 60064-6217. Phone: (847) 937-5933. Fax: (847) 938-2756. E-mail: Hongmei.Mo{at}abbott.com.

Antimicrobial Agents and Chemotherapy, October 2005, p. 4305-4314, Vol. 49, No. 10
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.10.4305-4314.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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