Experimental systems for the study of hepadnavirus and hepatitis delta virus infections

Mason, William S.; Taylor, John M.

doi:10.1002/hep.1840090420

Cited by 39 publications

(15 citation statements)

References 123 publications

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“…With this aim, new antiviral compounds are usually assessed in experimental models of hepadnavirus replication (30), including in vitro hepatocyte culture (10,19,31) and the convenient in vivo model of duck HBV (DHBV) infection (9,27,33,47). The woodchuck model of HBV infection (woodchuck hepatitis virus [WHV] infection) presents many features in common with the natural history of human HBV infection, including the development of chronic hepatitis and hepatocellular carcinoma (40,41).…”

mentioning

confidence: 99%

Antiviral Activity of β- l -2′,3′-Dideoxy-2′,3′-Didehydro-5-Fluorocytidine in Woodchucks Chronically Infected with Woodchuck Hepatitis Virus

Guerhier

Pichoud

Jamard

et al. 2001

Antimicrob Agents Chemother

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The L-nucleoside analog ␤-L-2,3-dideoxy-2,3-didehydro-5-fluorocytidine (␤-L-Fd4C) was first shown to exhibit potent activity against hepatitis B virus (HBV) in tissue culture and then to significantly inhibit viral spread during acute infection in the duck HBV model (F. Le Guerhier et al., Antimicrob. Agents Chemother. 44:111-122, 2000). We have therefore examined its antiviral activity in a mammalian model of chronic HBV infection, the woodchuck chronically infected with woodchuck hepatitis virus (WHV). Side-by-side comparison of ␤-L-Fd4C and lamivudine administered intraperitoneally during short-term and long-term protocols demonstrated a more profound inhibition of viremia in ␤-L-Fd4C-treated groups. Moreover, ␤-L-Fd4C induced a marked inhibition of intrahepatic viral DNA synthesis compared with that induced by lamivudine. Nevertheless, covalently closed circular (CCC) DNA persistence explained the lack of clearance of infected hepatocytes expressing viral antigens and the relapse of WHV replication after drug withdrawal. Liver histology showed a decrease in the inflammatory activity of chronic hepatitis in woodchucks receiving ␤-L-Fd4C. An electron microscopy study showed the absence of ultrastructural changes of hepatic mitochondria, biliary canaliculi, and bile ducts. However, a loss of weight was observed in all animals, whatever the treatment, as was a transient skin pigmentation in all woodchucks during ␤-L-Fd4C treatment. There was no evidence that lamivudine or ␤-L-Fd4C could prevent the development of hepatocellular carcinoma with the protocols used. These results indicate that ␤-L-Fd4C exhibits a more potent antiviral effect than lamivudine in the WHV model but was not able to eradicate CCC DNA and infected cells from the liver at the dosage and with the protocol used.Chronic hepatitis B virus (HBV) infection remains a major public health problem worldwide due to its natural history, which includes the progression to chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (25). The recent approval of lamivudine [␤-L(Ϫ)-2Ј,3Ј-dideoxy-3Ј-thiacytidine, also called 3TC or L(Ϫ)SddC] has opened new perspectives for the therapy of chronic hepatitis B. In all clinical trials, 3TC was shown to be well tolerated and to be a very potent inhibitor of HBV replication (7, 24). However, due to the long half-life of infected hepatocytes and the persistence of viral covalently closed circular (CCC) DNA in infected hepatocytes, long-term treatment is required to control or eradicate viral infection (29, 34). The spontaneous HBV genome variability gives rise to a progressive selection of drug-resistant variants in 16 to 43% of the patients after 1 year of therapy (7, 24). These mutations located in the conserved B and C domains of the HBV reverse transcriptase confer resistance to 3TC (2, 49).Therefore, the design and evaluation of new molecules with anti-HBV activity remain major goals. With this aim, new antiviral compounds are usually assessed in experimental models of hepadnavirus replication (30), includ...

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confidence: 99%

Antiviral Activity of β- l -2′,3′-Dideoxy-2′,3′-Didehydro-5-Fluorocytidine in Woodchucks Chronically Infected with Woodchuck Hepatitis Virus

Guerhier

Pichoud

Jamard

et al. 2001

Antimicrob Agents Chemother

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“…We have therefore characterized its antiviral activity in the duck hepatitis B virus (DHBV) infection model in comparison with lamivudine and other deoxycytidine analogs. This model provides relevant tools to study the mechanism of action of new antiviral compounds on the viral polymerase expressed in vitro, in primary hepatocyte cultures and in vivo in experimentally infected animals (1,4,8,20,25,42). In the studies reported herein, we give evidence that ␤-L-Fd4C suppresses DHBV reverse transcription and inhibits the initiation of infection as well as viral antigen expression in hepatocytes.…”

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confidence: 99%

Characterization of the Antiviral Effect of 2′,3′-Dideoxy-2′, 3′-Didehydro-β- l -5-Fluorocytidine in the Duck Hepatitis B Virus Infection Model

Guerhier

Pichoud

Guérret

et al. 2000

Antimicrob Agents Chemother

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Chronic hepatitis B virus (HBV) infection remains a major public health problem worldwide, with three hundred million chronic carriers of the virus, and its serious clinical consequences include liver cirrhosis and hepatocellular carcinoma (19). Unfortunately, alpha interferon therapy induces a sustained antiviral response in only 20 to 30% of the patients (12). The development of new nucleoside analogs, such as ␤-L(Ϫ)-2Ј,3Ј-dideoxy-3Ј-thiacytidine [L(Ϫ)SddC or 3TC or lamivudine] that exhibit a potent inhibitory effect on HBV reverse transcriptase activity and viral replication in vitro (2, 6, 31), has opened new avenues in the antiviral therapy of chronic hepatitis B. Results of phase II and phase III clinical trials have shown that administration of lamivudine results in a dramatic suppression of viral replication which is accompanied by an improvement in liver histology (16,27,44). However, because of the relatively low rate of anti-HBe seroconversion and of the special features of the viral kinetics, long-term therapy with a nucleoside analog is required to eradicate viral infection (16,28). Indeed, chronic HBV infection is characterized by a high rate of virus production, by the absence of a cytopathogenic effect (and therefore a long half-life of infected hepatocytes), and by the persistence of viral genomes as a covalently closed circular DNA (CCC DNA) in the nucleus of infected cells (9,26,28,36,40). Because of the spontaneous error rate of the viral reverse transcriptase, prolonged administration of a single nucleoside analog in chronically infected patients may select for the replication of resistant viral strains. The rate of selection of resistant mutants is 23% after 1 year of lamivudine treatment and increases to 38% at the end of the second year of therapy (16). The same observation has been made with long-term treatment with famciclovir, another inhibitor of HBV polymerase, and it was demonstrated that the resistant viruses harbor mutations in conserved domains of the viral reverse transcriptase (29,44).In order to design new strategies that combine several antiviral agents with different mechanisms of action to prevent the emergence of resistant strains, the development of new inhibitors of HBV replication is required (44). In the search for new potent antiviral agents, 2Ј,3Ј-dideoxy-2Ј,3Ј-didehydro-␤-L-5-fluorocytidine (␤-L-Fd4C) was found to exhibit a potent antiviral activity against human immunodeficiency virus and HBV replication in tissue culture (7,23). ␤-L-Fd4C was found to be at least 10 times more potent (50% inhibitory concentration [IC 50 ] at 1 nM) than lamivudine (IC 50 at 15 nM) on HBV DNA synthesis in the hepatoma cell line HepG2 2.2.15, and its triphosphate derivative specifically inhibited the virion associated HBV DNA polymerase activity (41). Detailed analysis of the intracellular metabolism of ␤-L-Fd4C revealed that the degree of phosphorylation and retention time of the triphosphate metabolites were higher than for lamivudine which may explain, at least in part, both the m...

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“…The interaction of aflatoxin and HBV has been examined in two of the animal models for which hepadna viruses have been identified, namely, the Pekin duck and woodchuck (37). In addition, various strains of transgenic mice expressing providing an different human HBV proteins have been developed (38)(39)(40) Carcinogenicity Studies…”

Section: Animal Modelsmentioning

confidence: 99%

Molecular Dosimetry of Aflatoxin Exposure: Contribution to Understanding the Multifactorial Etiopathogenesis of Primary Hepatocellular Carcinoma with Particular Reference to Hepatitis B Virus

Wild¹,

Jansen²,

Cova³

et al. 1993

Environmental Health Perspectives

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Aflatoxin exposure and hepatitis B virus infection have been implicated as major risk factors for primary hepatoceOlular carcinoma (PHC) in high-incidence regions ofthe world. Investigations using the assay ofaflatoxin bound to peripheral blood albumin have shown that exposure can occur throughout the life spanofthe individual, including during the perinatal period, in high-incidence areas such as The Gambia, Senegal, Kenya, and The People's Republic of China. The possibility of measuring aflatoxin exposure at the individual level permits an investigation ofthe putative mechanisms ofinteraction of this carcinogen with HBV in the etiopathogenesis of PHC. Aninal models, e.g., Pekin duck and HBV-transgenic mice, have also been used to study these questions, and the available data are reviewed.

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Experimental systems for the study of hepadnavirus and hepatitis delta virus infections

Cited by 39 publications

References 123 publications

Antiviral Activity of β- l -2′,3′-Dideoxy-2′,3′-Didehydro-5-Fluorocytidine in Woodchucks Chronically Infected with Woodchuck Hepatitis Virus

Antiviral Activity of β- l -2′,3′-Dideoxy-2′,3′-Didehydro-5-Fluorocytidine in Woodchucks Chronically Infected with Woodchuck Hepatitis Virus

Characterization of the Antiviral Effect of 2′,3′-Dideoxy-2′, 3′-Didehydro-β- l -5-Fluorocytidine in the Duck Hepatitis B Virus Infection Model

Molecular Dosimetry of Aflatoxin Exposure: Contribution to Understanding the Multifactorial Etiopathogenesis of Primary Hepatocellular Carcinoma with Particular Reference to Hepatitis B Virus

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