title: Treatment of chronic viral hepatitis in woodchucks by prolonged intrahepatic expression of interleukin-12.
abstract: 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 10(10) 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-gamma) upon IL-12 stimulation, while lymphocytes from woodchucks with high viremia failed to upregulate IFN-gamma 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 10(10) vg/ml. Interestingly, this therapy is able to break immunological tolerance to viral antigens in chronic WHV carriers.
authors.affiliation: Department of Gene Therapy and Hepatology, Center for Investigation in Applied Medicine (CIMA), Avda Pio XII 55, 31008 Pamplona, Spain.
authors.forename: Julien
authors.initials: J
authors.lastname: Crettaz
authors.forename: Itziar
authors.initials: I
authors.lastname: Otano
authors.forename: Laura
authors.initials: L
authors.lastname: Ochoa-Callejero
authors.forename: Laura
authors.initials: L
authors.lastname: Ochoa
authors.forename: Alberto
authors.initials: A
authors.lastname: Benito
authors.forename: Astrid
authors.initials: A
authors.lastname: Paneda
authors.forename: Igor
authors.initials: I
authors.lastname: Aurrekoetxea
authors.forename: Pedro
authors.initials: P
authors.lastname: Berraondo
authors.forename: Juan Roberto
authors.initials: JR
authors.lastname: Rodríguez-Madoz
authors.forename: Aurora
authors.initials: A
authors.lastname: Astudillo
authors.forename: Florian
authors.initials: F
authors.lastname: Kreppel
authors.forename: Stefan
authors.initials: S
authors.lastname: Kochanek
authors.forename: Juan
authors.initials: J
authors.lastname: Ruiz
authors.forename: Stephan
authors.initials: S
authors.lastname: Menne
authors.forename: Jesus
authors.initials: J
authors.lastname: Prieto
authors.forename: Gloria
authors.initials: G
authors.lastname: Gonzalez-Aseguinolaza
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006509:Hepatitis B / Q000276:immunology / Q000662:veterinary*; D017919:Hepatitis B Virus, Woodchuck / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000276:immunology*; D008099:Liver / Q000473:pathology / Q000821:virology; D008392:Marmota / Q000821:virology*; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA; D013601:T-Lymphocytes / Q000276:immunology; D014766:Viremia
chemical_list: D051858:Forkhead Transcription Factors; D018664:Interleukin-12; D007371:Interferon-gamma