Transmission of Type B Viral Hepatitis to Chimpanzees

Barker, Lewellys F.; Chisari, Francis V.; McGrath, Philip P.; Dalgard, Dan W.; Kirschstein, Ruth L.; Almeida, June D.; Edgington, Thomas S.; Sharp, D. G.; Petersont, Michael R.

doi:10.1093/infdis/127.6.648

Cited by 215 publications

(91 citation statements)

References 36 publications

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“…Starting 4 days after WHV infection, L-FMAU was present in culture medium at a 10 M concentration. Hepatocyte monolayers were harvested at 4,8,16,24,32, and 40 days after WHV infection and stored at Ϫ80°C for subsequent extraction of viral nucleic acids.…”

Section: Methodsmentioning

confidence: 99%

Kinetics of Hepadnavirus Loss from the Liver during Inhibition of Viral DNA Synthesis

Zhu

Yamamoto

Cullen

et al. 2001

J Virol

220

200

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Hepadnaviruses replicate by reverse transcription, which takes place in the cytoplasm of the infected hepatocyte. Viral RNAs, including the pregenome, are transcribed from a covalently closed circular (ccc) viral DNA that is found in the nucleus. Inhibitors of the viral reverse transcriptase can block new DNA synthesis but have no direct effect on the up to 50 or more copies of cccDNA that maintain the infected state. Thus, during antiviral therapy, the rates of loss of cccDNA, infected hepatocytes (1 or more molecules of cccDNA), and replicating DNAs may be quite different. In the present study, we asked how these losses compared when woodchucks chronically infected with woodchuck hepatitis virus were treated with L-FMAU [1-(2-fluoro-5-methyl-␤-L-arabinofuranosyl) uracil], an inhibitor of viral DNA synthesis. Viremia was suppressed for at least 8 months, after which drug-resistant virus began replicating to high titers. In addition, replicating viral DNAs were virtually absent from the liver after 6 weeks of treatment. In contrast, cccDNA declined more slowly, consistent with a half-life of ϳ33 to 50 days. The loss of cccDNA was comparable to that expected from the estimated death rate of hepatocytes in these woodchucks, suggesting that death of infected cells was one of the major routes for elimination of cccDNA. However, the decline in the actual number of infected hepatocytes lagged behind the decline in cccDNA, so that the average cccDNA copy number in infected cells dropped during the early phase of therapy. This observation was consistent with the possibility that some fraction of cccDNA was distributed to daughter cells in those infected hepatocytes that passed through mitosis.

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Section: Methodsmentioning

confidence: 99%

Kinetics of Hepadnavirus Loss from the Liver during Inhibition of Viral DNA Synthesis

Zhu

Yamamoto

Cullen

et al. 2001

J Virol

220

200

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“…My first opportunity to actively pursue this interest came when I was lucky enough to be part of a team at the National Institutes of Health that transmitted the hepatitis B virus (HBV) to chimpanzees. 1 Thus began a longstanding interest in the immunobiology of persistent human viral infections, especially those that infect the liver. I am greatly honored that this work has been recognized by the Rous-Whipple Award this year, giving me this opportunity to describe our current state of understanding of these infections.…”

Section: From the Department Of Molecular And Experimental Medicine mentioning

confidence: 99%

Viruses, Immunity, and Cancer: Lessons from Hepatitis B

Chisari

2000

The American Journal of Pathology

281

226

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“…Although chimpanzees are susceptible to both infections (5-7), their usage is limited for ethical and practical reasons (5). Other hepadnaviruses that infect ducks (8), woodchucks (9), and ground squirrels (10) have been widely used as surrogates to study HBV biology (1), but they are outbred and suffer from the limitations attendant to genetic heterogeneity, restricted reagents, and our understanding of the immunobiology of the hosts.…”

Section: Introductionmentioning

confidence: 99%

Human liver chimeric mice provide a model for hepatitis B and C virus infection and treatment

Bissig

Wieland²,

Tran³

et al. 2010

J. Clin. Invest.

316

317

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A paucity of versatile small animal models of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection has been an impediment to both furthering understanding of virus biology and testing antiviral therapies. We recently described a regulatable system for repopulating the liver of immunodeficient mice (specifically mice lacking fumaryl acetoacetate hydrolase [Fah], recombination activating gene 2 [Rag2], and the γ-chain of the receptor for IL-2 [Il-2rγ]) with human hepatocytes. Here we have shown that a high transplantation dose (3 × 10 6 to 5 × 10 6 human hepatocytes/mouse) generates a higher rate of liver chimerism than was previously obtained in these mice, up to 95% human hepatocyte chimerism. Mice with a high level of human liver chimerism propagated both HBV and HCV, and the HCV-infected mice were responsive to antiviral treatment. This human liver chimeric mouse model will expand the experimental possibilities for studying HBV and HCV infection, and possibly other human hepatotropic pathogens, and prove useful for antiviral drug testing.

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Transmission of Type B Viral Hepatitis to Chimpanzees

Cited by 215 publications

References 36 publications

Kinetics of Hepadnavirus Loss from the Liver during Inhibition of Viral DNA Synthesis

Kinetics of Hepadnavirus Loss from the Liver during Inhibition of Viral DNA Synthesis

Viruses, Immunity, and Cancer: Lessons from Hepatitis B

Human liver chimeric mice provide a model for hepatitis B and C virus infection and treatment

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