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Antimicrobial Agents and Chemotherapy, December 2006, p. 3984-3991, Vol. 50, No. 12
0066-4804/06/$08.00+0     doi:10.1128/AAC.00199-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Novel Alpha Interferon (IFN-{alpha}) Variant with Improved Inhibitory Activity against Hepatitis C Virus Genotype 1 Replication Compared to IFN-{alpha}2b Therapy in a Subgenomic Replicon System{triangledown}

Vanessa Escuret,1 Amaury Martin,1 David Durantel,1 Romain Parent,1 Olivier Hantz,1 Christian Trépo,1 Thierry Menguy,2 Emmanuel Bottius,2 Jerome Dardy,2 Jean Maral,2 Jean Louis Escary,2 and Fabien Zoulim1*

INSERM, U271, Laboratoire des virus hépatiques et pathologies associées, 151 cours Albert Thomas, 69003 Lyon, and Université Lyon 1, Faculté de Médecine Laennec, 69008 Lyon, France,1 GenOdyssee SA, 4 Rue Pierre Fontaine, 91058 Evry Cedex, France2

Received 15 February 2006/ Returned for modification 30 March 2006/ Accepted 15 September 2006

Hepatitis C virus (HCV) treatment is based on the association of pegylated alpha interferon (IFN-{alpha}) and ribavirin. To improve the level of sustained virological response to treatment, especially in patients infected with HCV genotype 1, new IFNs with improved efficacy and toxicity profiles may be developed. In this report, we show that, in the BM4-5 cell line harboring an HCV subgenomic replicon, a novel and naturally occurring human IFN-{alpha}17 variant, GEA007.1, which was discovered by using an original population genetics-based drug discovery approach, inhibits HCV genotype 1 RNA replication more efficiently than does IFN-{alpha}2b. Moreover, we show that complete viral clearance is obtained in BM4-5 cells after long-term treatment with GEA007.1, while HCV subgenomic RNA is still detected in cells treated with other IFN-{alpha} variants or with standard IFN-{alpha}2b. Eventually, we demonstrate that the better inhibitory activity of GEA007.1 compared to that of standard IFN-{alpha} is likely to be due to stronger and faster activation of the JAK-STAT signaling pathway and to broader expression of IFN-{alpha}-responsive genes in cells. Our results demonstrate a superior inhibitory activity of GEA007.1 over that of IFN-{alpha}2b in the HCV replicon system. Clinical trials are required to determine whether GEA007.1 could be a potent "next generation" IFN for the treatment of HCV infection, especially in nonresponders or relapsing patients infected with HCV genotype 1 who currently represent a clinical unmet need.

* Corresponding author. Mailing address: INSERM, U271, 151 cours Albert Thomas, 69424, Lyon Cedex 03, France. Phone: 33-472 681 970. Fax: 33-472 681 971. E-mail: zoulim{at}lyon.inserm.fr.

{triangledown} Published ahead of print on 25 September 2006.

Antimicrobial Agents and Chemotherapy, December 2006, p. 3984-3991, Vol. 50, No. 12
0066-4804/06/$08.00+0     doi:10.1128/AAC.00199-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.





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