The woodchuck as an animal model for pathogenesis and therapy of chronic hepatitis B virus infection

Abstract

This review describes the woodchuck and the woodchuck hepatitis virus (WHV) as an animal model for pathogenesis and therapy of chronic hepatitis B virus (HBV) infection and disease in humans. The establishment of woodchuck breeding colonies, and use of laboratory-reared woodchucks infected with defined WHV inocula, have enhanced our understanding of the virology and immunology of HBV infection and disease pathogenesis, including major sequelae like chronic hepatitis and hepatocellular carcinoma. The role of persistent WHV infection and of viral load on the natural history of infection and disease progression has been firmly established along the way. More recently, the model has shed new light on the role of host immune responses in these natural processes, and on how the immune system of the chronic carrier can be manipulated therapeutically to reduce or delay serious disease sequelae through induction of the recovery phenotype. The woodchuck is an outbred species and is not well defined immunologically due to a limitation of available host markers. However, the recent development of several key host response assays for woodchucks provides experimental opportunities for further mechanistic studies of outcome predictors in neonatal- and adult-acquired infections. Understanding the virological and immunological mechanisms responsible for resolution of self-limited infection, and for the onset and maintenance of chronic infection, will greatly facilitate the development of successful strategies for the therapeutic eradication of established chronic HBV infection. Likewise, the results of drug efficacy and toxicity studies in the chronic carrier woodchucks are predictive for responses of patients chronically infected with HBV. Therefore, chronic WHV carrier woodchucks provide a well-characterized mammalian model for preclinical evaluation of the safety and efficacy of drug candidates, experimental therapeutic vaccines, and immunomodulators for the treatment and prevention of HBV disease sequelae.

Chemoimmunotherapy of Chronic Hepatitis B Virus Infection in the Woodchuck Model Overcomes Immunologic Tolerance and Restores T-Cell Responses to Pre-S and S Regions of the Viral Envelope Protein

“…One new strategy has been modeled with woodchucks (Marmota monax) chronically infected with the woodchuck hepatitis virus (WHV) (12,21,29,44). It involves combination chemoimmunotherapy using potent experimental antiviral drugs and vaccine immunizations.…”

“…Nucleoside and nucleotide analogs, such as lamivudine, entecavir, and adefovir dipivoxil, produce antiviral effects with minimal toxicity, but there is the risk of a relapse if treatment is discontinued and the emergence of drug-resistant variants with continued treatment (25). Accordingly, chronic HBV carriers could benefit immensely from more-effective therapies.One new strategy has been modeled with woodchucks (Marmota monax) chronically infected with the woodchuck hepatitis virus (WHV) (12,21,29,44). It involves combination chemoimmunotherapy using potent experimental antiviral drugs and vaccine immunizations.…”

Primary Occult Hepadnavirus Infection Induces Virus-Specific T-Cell and Aberrant Cytokine Responses in the Absence of Antiviral Antibody Reactivity in the Woodchuck Model of Hepatitis B Virus Infection

“…The infection of eastern North American woodchucks (Marmota monax) with woodchuck hepatitis virus (WHV), a member of the Hepadnaviridae family (44,47), provides a natural and highly valuable laboratory model of HBV infection. The molecular, virological, and pathological events that follow WHV invasion are highly compatible to those induced by HBV in humans.…”

Assessment of Increased Serum Aminotransferases in a Managed Atlantic Bottlenose Dolphin (Tursiops Truncatus) Population

“…Etiologies of hepatitis have been extensively studied in terrestrial mammalian species, including dogs (Boomkens et al, 2004), humans (Bondesson and Saperston, 1996), and woodchucks (Menne and Cote, 2007). Causes of chronic hepatitis were once categorized as viral, autoimmune, or metabolic (nonalcoholic fatty liver syndrome); however, all three causes may occur concurrently or in succession to each other (Hui et al, 2002;Lecube et al, 2004;Bugianesi et al, 2006;Nobili et al, 2006;Strassburg, 2006;Wu et al, 2006).…”