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Journal of Virology, March 2009, p. 2663-2674, Vol. 83, No. 6
0022-538X/09/$08.00+0     doi:10.1128/JVI.02384-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Treatment of Chronic Viral Hepatitis in Woodchucks by Prolonged Intrahepatic Expression of Interleukin-12

Julien Crettaz,¹ Itziar Otano,¹ Laura Ochoa,¹ Alberto Benito,² Astrid Paneda,¹ Igor Aurrekoetxea,¹ Pedro Berraondo,¹ Juan Roberto Rodríguez-Madoz,¹ Aurora Astudillo,³ Florian Kreppel,⁴ Stefan Kochanek,⁴ Juan Ruiz,⁵ Stephan Menne,⁶ Jesus Prieto,^1,7 and Gloria Gonzalez-Aseguinolaza^1*

Division of Hepatology and Gene Therapy, Center for Investigation in Applied Medicine (CIMA), University of Navarra, 31008 Pamplona, Spain,¹ Department of Radiology, University Clinic/Hospital, University of Navarra, 31008 Pamplona, Spain,² Department of Pathology, Hospital Universitario Central de Asturias, 33006 Oviedo, Spain,³ Division of Gene Therapy, University of Ulm, 89081 Ulm, Germany,⁴ DIGNA Biotech, 28003 Madrid, Spain,⁵ Gastrointestinal Unit, Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853,⁶ Liver Unit, University Clinic and CIBERehd, University of Navarra, 31008 Pamplona, Spain⁷

Received 17 November 2008/ Accepted 22 December 2008

Chronic hepatitis B is a major cause of liver-related death worldwide. Interleukin-12 (IL-12) induction accompanies viral clearance in chronic hepatitis B virus infection. Here, we tested the therapeutic potential of IL-12 gene therapy in woodchucks chronically infected with woodchuck hepatitis virus (WHV), an infection that closely resembles chronic hepatitis B. The woodchucks were treated by intrahepatic injection of a helper-dependent adenoviral vector encoding IL-12 under the control of a liver-specific RU486-responsive promoter. All woodchucks with viral loads below 10¹⁰ viral genomes (vg)/ml showed a marked and sustained reduction of viremia that was accompanied by a reduction in hepatic WHV DNA, a loss of e antigen and surface antigen, and improved liver histology. In contrast, none of the woodchucks with higher viremia levels responded to therapy. The antiviral effect was associated with the induction of T-cell immunity against viral antigens and a reduction of hepatic expression of Foxp3 in the responsive animals. Studies were performed in vitro to elucidate the resistance to therapy in highly viremic woodchucks. These studies showed that lymphocytes from healthy woodchucks or from animals with low viremia levels produced gamma interferon (IFN-) upon IL-12 stimulation, while lymphocytes from woodchucks with high viremia failed to upregulate IFN- in response to IL-12. In conclusion, IL-12-based gene therapy is an efficient approach to treat chronic hepadnavirus infection in woodchucks with viral loads below 10¹⁰ vg/ml. Interestingly, this therapy is able to break immunological tolerance to viral antigens in chronic WHV carriers.

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* Corresponding author. Mailing address: Department of Gene Therapy and Hepatology, Center for Investigation in Applied Medicine (CIMA), Avda Pio XII 55, 31008 Pamplona, Spain. Phone: 34 948194700. Fax: 34 948194717. E-mail: ggasegui{at}unav.es

Published ahead of print on 30 December 2008.

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Journal of Virology, March 2009, p. 2663-2674, Vol. 83, No. 6
0022-538X/09/$08.00+0     doi:10.1128/JVI.02384-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

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