ReviewThe human liver-uPA-SCID mouse: A model for the evaluation of antiviral compounds against HBV and HCV
Introduction
The hepatitis B virus (HBV) and hepatitis C virus (HCV) are hepatotropic viruses that represent a serious global health problem. The number of chronically infected subjects is estimated at 360 million for HBV and 170 million for HCV and annually these pathogens kill more than 1.5 million people worldwide (Alter, 2003, Shepard et al., 2005). In the past decade substantial progress has been made in treating these chronic infections but no definitive cure is yet available and today's standard treatment for HCV causes severe side effects. Therefore huge research efforts are being made to develop new antiviral compounds that are more efficacious and better tolerated.
The efficacy of new antiviral compounds is now primarily evaluated in cell culture (Lindenbach et al., 2005, Lohmann et al., 1999, Wakita et al., 2005, Zhong et al., 2005, Zoulim, 2006). However, before the toxicity and activity of investigational new drugs are assessed in humans, preclinical evaluation needs to be performed in relevant animal models. Because both HBV and HCV have a very narrow tropism, preclinical in vivo studies can only be performed in chimpanzees. For obvious financial and ethical reasons, pharmaceutical companies have not always been able to take this important step. In the last decades a variety of animal species have been examined for their permissiveness for HBV and HCV, and several transgenic and chimeric animal models have been developed. In this review, we will give a detailed description of the “human liver-uPA-SCID” mouse, which appears currently to be the most valuable small animal model for the study of viral hepatitis, and compare it to other animal models. In addition, we will provide an overview of how this model has already contributed to the development of new antiviral strategies against HBV and HCV.
Section snippets
Animal models for the study of HBV and HCV
For decades chimpanzees have been used to study the immunobiology as well as candidate therapies for both HBV (Prince and Brotman, 2001) and HCV infection (Bukh, 2004). Although humans and chimpanzees share more than 98% of their genome sequences, there are some marked differences between these two species that have an influence on disease pattern and outcome (Muchmore, 2001). Chimpanzees and humans do not share any HLA class I alleles; e.g. HLA-A2 alleles are totally absent in chimps but
The chimeric uPA-SCID mouse
In 1990, Dr. Brinster's team developed a transgenic mouse to study the pathophysiology of plasminogen hyperactivation and to evaluate new therapeutic protocols for bleeding disorders (Heckel et al., 1990). This transgenic mouse carried the mouse urokinase-type plasminogen activator (uPA) gene under the control of the mouse albumin enhancer/promotor. The overexpression of the uPA gene in the liver resulted in high plasma uPA levels and hypofibrinogenemia, which led to severe and sometimes fatal
HBV and HCV infection of human liver chimeric mice
Dandri et al. (2001) showed that chimeric mice were susceptible to HBV infection. Although the livers of the infected animals contained less than 15% human hepatocytes, an HBV infection was established after injection of serum from a chronic HBV carrier. Active replication of the virus was demonstrated by the presence of viral DNA in the serum of the infected mice (4.5 to 10 × 108 genome equivalents/ml), and was confirmed by immunohistochemical detection of HBcAg in liver sections. We have
Neutralizing antibodies against HCV
Using different cell culture models, neutralizing antibodies have been detected in the plasma of both acute and chronic HCV patients (Logvinoff et al., 2004, Yu et al., 2004) but their exact role in disease outcome remains unclear (Kaplan et al., 2007, Lavillette et al., 2005, Pestka et al., 2007). Using the chimeric mouse model we have shown that neutralizing antibodies can prevent an HCV infection in vivo (Vanwolleghem et al., 2008). Polyclonal antibodies were isolated from serum collected in
Interferon alpha
The first antiviral drug that was approved by the FDA for the treatment of chronic HCV patients was interferon alpha. Therefore it was an obvious choice to validate the usefulness of the chimeric mouse model for anti-HCV drug testing with this compound. A 10–14 day treatment of genotype 1 infected mice with 1350 IU/(g.day) of IFN-α2b, a 10-fold higher dose than what is administered to patients, resulted in a 10-fold drop in viral titer (Kneteman et al., 2006). When the treatment was extended to
Conclusions and prospects
The generation of the human liver-uPA-SCID mouse represents a major step forward for the study of human hepatotropic viruses. The transplanted human hepatocytes reside in their natural environment (the liver) and maintain normal functions. More importantly, these animals can be infected in vivo with natural HBV and HCV in a reproducible manner and these infections always show a chronic evolution. We have succeeded in infecting animals with HCV of all six genotypes (unpublished data). The model
Acknowledgements
The authors’ work described in this review was supported by the Ghent University by a Concerted Action Grant (01G00507) and by the Belgian State via the Interuniversity Attraction Poles Program (P6/36—HEPRO). PM is supported by a postdoctoral fellowship grant from The Research Foundation Flanders (FWO-Vlaanderen). We thank Dr. Mike Bray for critically reading this review and providing helpful suggestions.
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