Chronic infection with hepatitis B viruses and antiviral drug evaluation in uPA mice after liver repopulation with tupaia hepatocytes

Dandri, Maura; Burda, Martin R.; Zuckerman, David M.; Wursthorn, Karsten; Matschl, Urte; Pollok, Joerg M.; Rogiers, Xavier; Gocht, Andreas; Köck, Josef; Blum, Hubert E.; Weizsäcker, Fritz von; Petersen, J.

doi:10.1016/j.jhep.2004.09.021

Cited by 67 publications

(26 citation statements)

References 22 publications

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“…The lack of a small animal model susceptible to HBV infection has hampered the development of simple methods to evaluate new therapeutic compounds. In this context, we and others have developed a model of mice that are susceptible to HBV infection; the immunodeficient urokinase-type plasminogen activator (uPA/SCID) transgenic mouse, described as being a potent host for liver repopulation by human hepatocytes and HBV infection [17]–[19], [20], [21]. Human hepatocytes engrafted in the liver of uPA/SCID mice continue to express many of the human enzymes implicated in detoxification metabolism, so that the antiviral capacity of therapeutic molecules directed against hepatitis viruses can be assessed [18], [20].…”

Section: Introductionmentioning

confidence: 99%

Antiviral Activity of Bay 41-4109 on Hepatitis B Virus in Humanized Alb-uPA/SCID Mice

et al. 2011

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Current treatments for HBV chronic carriers using interferon alpha or nucleoside analogues are not effective in all patients and may induce the emergence of HBV resistant strains. Bay 41-4109, a member of the heteroaryldihydropyrimidine family, inhibits HBV replication by destabilizing capsid assembly. The aim of this study was to determine the antiviral effect of Bay 41-4109 in a mouse model with humanized liver and the spread of active HBV. Antiviral assays of Bay 41-4109 on HepG2.2.15 cells constitutively expressing HBV, displayed an IC50 of about 202 nM with no cell toxicity. Alb-uPA/SCID mice were transplanted with human hepatocytes and infected with HBV. Ten days post-infection, the mice were treated with Bay 41-4109 for five days. During the 30 days of follow-up, the HBV load was evaluated by quantitative PCR. At the end of treatment, decreased HBV viremia of about 1 log(10) copies/ml was observed. By contrast, increased HBV viremia of about 0.5 log(10) copies/ml was measured in the control group. Five days after the end of treatment, a rebound of HBV viremia occurred in the treated group. Furthermore, 15 days after treatment discontinuation, a similar expression of the viral capsid was evidenced in liver biopsies. Our findings demonstrate that Bay 41-4109 displayed antiviral properties against HBV in humanized Alb-uPA/SCID mice and confirm the usefulness of Alb-uPA/SCID mice for the evaluation of pharmaceutical compounds. The administration of Bay 41-4109 may constitute a new strategy for the treatment of patients in escape from standard antiviral therapy.

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Section: Introductionmentioning

confidence: 99%

Antiviral Activity of Bay 41-4109 on Hepatitis B Virus in Humanized Alb-uPA/SCID Mice

et al. 2011

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“…The functionality of transplanted hepatocytes was later attested by their susceptibility to infection with 1000 and 1100 h at the ages indicated. All animals were maintained under pathogen-free conditions and were HBV (11,26,37,39), HCV (25,26,40,41), and Plasmodium falciparum (28). treated in accordance with European Union regulations on animal care.…”

Section: Introductionmentioning

confidence: 99%

Rescue of Fertility in Homozygous Mice for the Urokinase Plasminogen Activator Transgene by the Transplantation of Mouse Hepatocytes

et al. 2008

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Development of the urokinase plasminogen activator/SCID (uPA/SCID) transgenic mouse model has opened new perspectives for the study of different biological mechanisms such as liver regeneration, stem cell differentiation, and human hepatic pathogens. We observed that homozygous uPA/SCID mice (uPA +/+ /SCID) had a small offspring, indicating a fertility defect. The goal of this study was thus to rescue the fertility of homozygous uPA mice. A deregulation of ovarian function with an absence of corpus luteum was observed in female uPA +/+ /SCID mice. In male uPA +/+ /SCID mice, a decrease of the weight of the testes, epididymis, seminal vesicle, and prostate was measured. This was associated with an absence of seminal and prostatic secretions and a reduction in testicular sperm production. We hypothesized that the infertility of mice was the consequence of uPA-induced liver injury. Thus, in order to rescue liver function, hepatocytes from mice negative for the uPA transgene were transplanted into uPA +/+ /SCID mice. Thirty days after cell transplantation, the livers of transplanted uPA +/+ /SCID mice were totally repopulated and presented a normal morphology. Furthermore, transplantation restored normal body weight, life span, and reproductive organ function.In conclusion, we demonstrated that the transplantation of uPA +/+ /SCID mice with healthy hepatocytes was sufficient to rescue the reproductive capacity of female and male uPA homozygous animals, highlighting the importance of normal liver function to reproductive capability.Key words: Hepatocyte transplantation; Fertility; uPA/SCID mice; Cell therapy INTRODUCTIONHepatitis B virus (HBV), hepatitis C virus (HCV), and Plasmodium are the three major hepatic pathogens and each year cause close on 10 million deaths throughUrokinase-type plasminogen activator (uPA) transgenic mice were first described in 1990 by Heckel et al.out the world. These pathogens require fully functional human hepatocytes for their development. Unfortu-(16). The overexpression of uPA protein in hepatocytes results in the activation of plasminogen to plasmin, which nately, hepatoma cell lines are difficult to infect and primary hepatocytes in culture do not retain their differentiis cytotoxic and gives rise to a continuous liver regeneration process (8). Under these conditions, hepatocytes ated function, thus limiting the value of these in vitro models. In vivo, the lack of a small-animal model susthat lose the transgene by somatic reversion, as well as healthy transplanted hepatocytes, have a strong survival ceptible to infection by human hepatotrope pathogens has hampered the development of simple methods to advantage over resident cells (32,33,35). The uPA/SCID mouse model has rapidly become an essential model for evaluate new therapeutic compounds. uPA transgenic mice were backcrossed on an immunodeficient backthe study of different biological mechanisms such as liver regeneration (3,35,42,43), carcinogenesis (34), cell ground (SCID or RAG-2 mice) to obtain a mouse model that would toler...

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“…Human chimeric liver mice have been used to evaluate HBV antivirals in vivo, including polymerase inhibitors such as lamivudine, entecavir and adefovir (Bissig et al, 2010; Dandri et al, 2005; Tsuge et al, 2005) and entry inhibitors such as Myrcludex-B, which is derived from the HBV large S protein (Oehler et al, 2014; Petersen et al, 2008). This model is also used to study HBV covalently closed circular DNA (cccDNA) biology in vivo (Lutgehetmann et al, 2010).…”

Section: Human-murine Liver Chimeric Mouse Modelsmentioning

confidence: 99%

Modeling hepatitis B virus infection, immunopathology and therapy in mice

Liu

Bility

et al. 2015

Antiviral Research

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Despite the availability of a preventive vaccine, chronic hepatitis B virus (HBV) infection-induced liver diseases continue to be a major global public health problem. HBV naturally infects only humans and chimpanzees. This narrow host range has hindered our ability to study the characteristics of the virus and how it interacts with its host. It is thus important to establish small animal models to study HBV infection, persistence, clearance and the immunopathogenesis of chronic hepatitis B. In this review, we briefly summarize currently available animal models for HBV research, then focus on mouse models, especially the recently developed humanized mice that can support HBV infection and immunopathogenesis in vivo. This article is part of a symposium in Antiviral Research on “From the discovery of the Australia antigen to the development of new curative therapies for hepatitis B: an unfinished story.”

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Chronic infection with hepatitis B viruses and antiviral drug evaluation in uPA mice after liver repopulation with tupaia hepatocytes

Cited by 67 publications

References 22 publications

Antiviral Activity of Bay 41-4109 on Hepatitis B Virus in Humanized Alb-uPA/SCID Mice

Antiviral Activity of Bay 41-4109 on Hepatitis B Virus in Humanized Alb-uPA/SCID Mice

Rescue of Fertility in Homozygous Mice for the Urokinase Plasminogen Activator Transgene by the Transplantation of Mouse Hepatocytes

Modeling hepatitis B virus infection, immunopathology and therapy in mice

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