The Woodchuck: An Animal Model for Hepatitis B Virus Infection in Man

Roggendorf, Michael; Tolle, Tanja K.

doi:10.1159/000150418

Cited by 108 publications

(71 citation statements)

References 11 publications

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“…Furthermore, chronic hepatitis is common in these animals and persistent infection is also associated with the development of hepatocellular carcinoma. 26 Moreover, we chose to use in vivo infected hepatocytes because this reflects more properly the virus production mechanisms and viral load commonly found in chronically infected patients in need of antiviral therapies. In our experimental conditions, woodchuck hepatocytes supported viral replication, and secretion of virus particles remained high throughout the study.…”

Section: Discussionmentioning

confidence: 99%

Increased hepatocyte turnover and inhibition of woodchuck hepatitis B virus replication by adefovir In vitro do not lead to reduction of the closed circular DNA

et al. 2000

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The aim of this study was to evaluate the inhibitory effect of the nucleotide analogue adefovir on woodchuck hepatitis B virus (WHV) replication and, in particular, to determine whether the pool of covalently closed circular DNA (cccDNA) could be reduced by adefovir treatment in primary cultures of woodchuck hepatocytes isolated from a chronic carrier. Strong reduction of WHV-DNA synthesis (90%) and secretion (up to 98%) was observed with all 3 doses of adefovir used (1, 10, and 100 mol/L), whereas in the absence of the drug, high amounts of viral particles were continuously secreted in the culture medium until the end of the study (27 days). Secretion of envelope proteins and viral RNA levels remained constant both in the adefovirtreated and -untreated cultures for the entire course of the study. Intracellular core protein levels declined by approximately 50% in all the cultures, independent of adefovir treatment. There was no indication of cccDNA loss in the adefovir-treated hepatocyte cultures even when cell turnover was induced for 14 days by the addition of epidermal growth factor (EGF) to the culture medium. Our data show that adefovir has a very strong inhibitory effect on WHV-DNA synthesis in chronically infected primary hepatocyte cultures and indicate that cccDNA is a very stable molecule that appears to be efficiently transmitted to the dividing hepatocytes. (HEPATOLOGY 2000;32:139-146.)Persistent infection with hepatitis B virus (HBV) continues to be a major health problem as it is associated with various degrees of liver damage, cirrhosis, and hepatocellular carcinoma. Despite the existence of an effective vaccine, more than 350 million people are infected worldwide. 1,2 Current treatment regimens primarily rely on interferon alfa therapy. However, interferon treatment is associated with a variety of side effects and has been successful in only approximately one third of the patients, being very poorly effective in individuals with perinatally acquired HBV infection. In recent years, a variety of new anti-HBV agents have been developed, and these are currently evaluated in clinical trials. 3,4 Because HBV replication proceeds through reverse transcription, treatment with inhibitors of HBV reverse transcriptase is a very attractive option.During hepadnavirus infection, the relaxed circular partially double stranded DNA genome is transported to the nucleus of the hepatocyte, where it is converted into a covalently closed circular molecule, named cccDNA, which serves as template for the transcription of all viral RNAs. 5 The synthesis of the new relaxed circular viral DNA genome is mediated by the viral P-protein, which has reverse transcriptase and DNA-dependent DNA polymerase activity. Synthesis of the viral DNA takes place in the cytoplasm of the hepatocytes within immature nucleocapsids. 6 To establish a sufficient pool of nuclear cccDNA, some of the newly synthesized viral DNAs need to be retransported to the nucleus of the infected hepatocyte. 7 Therefore, the replicative forms of viral DNA are a...

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Section: Discussionmentioning

confidence: 99%

Increased hepatocyte turnover and inhibition of woodchuck hepatitis B virus replication by adefovir In vitro do not lead to reduction of the closed circular DNA

et al. 2000

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“…3 WHV infection of its natural host woodchuck (Marmota monax) resembles HBV infection in humans regarding the major virological and immunological aspects as well as associated diseases, including chronic hepatitis and HCC. [3][4][5][6][7] The chronically WHV-infected woodchuck model thus represents an informative animal model to study the immunopathogenesis of HBV infection and develop therapeutic strategies combating HBV-related diseases. Therefore, basic information about and the availability of woodchuck-specific cytokines/chemokines are critical.…”

Section: Introductionmentioning

confidence: 99%

Characterization of interleukin 8 in woodchucks with chronic hepatitis B and hepatocellular carcinoma

Liu

et al. 2008

Genes Immun

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The eastern woodchuck, Marmota monax, represents a useful animal model to study hepatitis B virus infection in humans. However, immunological studies in this model have been impeded by a lack of basic information about the components of the immune system such as cytokines and chemokines. To clarify the role(s) of interleukin 8 (IL-8) in chronic hepatitis B and hepatocellular carcinoma (HCC) in the woodchuck model, we cloned and characterized the woodchuck IL-8 cDNA and genomic DNA. Sequence analysis revealed that the organization of the wk-IL-8 gene is similar to that of the human IL-8 gene and consists of four exons and three introns. Woodchuck IL-8 protein exhibits the conserved ELRCXC motif of IL-8 and shows 87, 82, 82 and 79% similarity with rabbit, ovine, bovine and human IL-8 proteins, respectively. The biological activity of wk-IL-8 was demonstrated using neutrophil chemotaxis assays. Wk-IL-8 could be readily detected in both tumor and non-tumor tissues with higher expression in the non-tumor tissues in most cases. The results from this study will facilitate the investigation of IL-8 in the immunopathogenesis of hepadnavirus-related diseases by the woodchuck model.

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“…To date most models of virus dynamics were developed to gain understanding of the dynamics of the virus and infected target cells, and have not incorporated the pharmacokinetic and pharmacodynamic parameters of pharmacological agents used in their treatment. Consequently, these models were not designed to predict virus depletion profiles as a function of dose regimen.Woodchuck hepatitis virus (WHV) is a member of the hepadnavirus family that includes duck hepatitis virus, ground squirrel hepatitis virus and HBV (Mason & Taylor, 1989;Roggendorf & Tolle, 1995). WHV-infected woodchucks are one of the most useful animal models for studying the pathology of HBV and for the development of antiviral nucleosides for treating HBV infections (Korba et al, 1987(Korba et al, , 2000aMason & Taylor, 1989;Seeger et al, 1991;Kajino et al, 1994;Roggendorf & Tolle, 1995;Schinazi et al, 1997Schinazi et al, ,1999Hurwitz et al, 1998;Tennant et al, 1998).…”

mentioning

confidence: 99%

“…WHV-infected woodchucks are one of the most useful animal models for studying the pathology of HBV and for the development of antiviral nucleosides for treating HBV infections (Korba et al, 1987(Korba et al, , 2000aMason & Taylor, 1989;Seeger et al, 1991;Kajino et al, 1994;Roggendorf & Tolle, 1995;Schinazi et al, 1997Schinazi et al, ,1999Hurwitz et al, 1998;Tennant et al, 1998). Nowak et al (1996) used a system of three differential equations that incorporated viral loads, the number of …”

mentioning

confidence: 99%

Viral Pharmacodynamic Model for (–)-β-2′,3′-Dideoxy-5-Fluoro-3′-Thiacytidine (Emtricitabine) in Chronically Infected Woodchucks

Hurwitz

Tennant

Korba

et al. 2002

Antivir Chem Chemother

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There is a need for models that can be used to predict the dynamics of virus depletion in hepatitis B virus (HBV)-infected individuals for use in early dose-ranging studies with nucleoside analogues that inhibit virus polymerase/ reverse transcriptase (RT), such as the triphosphate of lamivudine and the diphosphate of adefovir. To date most models of virus dynamics were developed to gain understanding of the dynamics of the virus and infected target cells, and have not incorporated the pharmacokinetic and pharmacodynamic parameters of pharmacological agents used in their treatment. Consequently, these models were not designed to predict virus depletion profiles as a function of dose regimen.Woodchuck hepatitis virus (WHV) is a member of the hepadnavirus family that includes duck hepatitis virus, ground squirrel hepatitis virus and HBV (Mason & Taylor, 1989;Roggendorf & Tolle, 1995). WHV-infected woodchucks are one of the most useful animal models for studying the pathology of HBV and for the development of antiviral nucleosides for treating HBV infections (Korba et al., 1987(Korba et al., , 2000aMason & Taylor, 1989;Seeger et al., 1991;Kajino et al., 1994;Roggendorf & Tolle, 1995;Schinazi et al., 1997Schinazi et al., ,1999Hurwitz et al., 1998;Tennant et al., 1998). Nowak et al. (1996) used a system of three differential equations that incorporated viral loads, the number of

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The Woodchuck: An Animal Model for Hepatitis B Virus Infection in Man

Cited by 108 publications

References 11 publications

Increased hepatocyte turnover and inhibition of woodchuck hepatitis B virus replication by adefovir In vitro do not lead to reduction of the closed circular DNA

Increased hepatocyte turnover and inhibition of woodchuck hepatitis B virus replication by adefovir In vitro do not lead to reduction of the closed circular DNA

Characterization of interleukin 8 in woodchucks with chronic hepatitis B and hepatocellular carcinoma

Viral Pharmacodynamic Model for (–)-β-2′,3′-Dideoxy-5-Fluoro-3′-Thiacytidine (Emtricitabine) in Chronically Infected Woodchucks

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