**4. Concluding remarks**

146 Liver Regeneration

interferon alpha failed to induce ISGs (MxA, OAS, TAP-1) in HBV infected hepatocytes, validating the model for the study of direct interaction between virus and host cells

Petersen et al., using the flexibility of the uPA mouse model, which could be repopulated either by Tupaia belangeri or human hepatocytes and infected by Wooly Monkey HBV or HBV respectively, have tested inhibitors of viral entry (Petersen et al 2008). In both systems, the authors showed that the treatment of repopulated mice with acylated HBV preS-derived lipopeptides prevented viral infection. This alternative approach could benefit patients undergoing liver transplantation to prevent vertical transmission as well as reinfection.

This model can establish long lasting chronic infections and constitute a perfect model to study anti-retroviral treatments. Indeed, it has been validated in different reports showing a good responsiveness to several reverse transcriptase inhibitors (lamivudine, adefovil dipivoxil) (Dandri et al 2005; Tsuge et al 2005). Others steps of viral replication can be targeted, it has been demonstrated that in infected mice HAP BAY 41-4109 (inhibition of capsid formation) was able to diminish HBV viremia (Brezillon et al 2011). Finally, the presence of HBV cccDNA in nucleus of infected human hepatocytes will allow testing new therapeutic approaches to clear hepatocytes or to control transcription from cccDNA

Concerning HCV, infected humanized mice have been used to demonstrate antiviral activity of several molecules, (IFNα2b, BILN2061, Telaprevir, HCV-796) that were already used in clinic, or in pre-clinical trials (Kamiya et al 2010; Kneteman et al 2006; Kneteman et al 2009; Vanwolleghem et al 2007). All these molecules have demonstrated antiviral effect against HCV. Moreover the model has permitted to describe cardio-toxicity of BILN2061, confirming the perfect suitability of humanized mice for antiviral therapy evaluation. This model can also been used to study susceptibility of different viral recombinant strains to actual treatments. This will allow strategies from "bench to bedside" to design specific

As for HBV, the design of inhibitors targeting several steps of HCV replication is the key to treat patients. In addition to protease and polymerase inhibitors, some groups tried to target viral entry. Meuleman et al have demonstrated the ability of antibodies directed against cellular surface molecules (CD81 and SR-B1) involved in virus entry to protect human hepatocytes from HCV infection (Meuleman et al 2008; Meuleman et al 2011a; Meuleman et al 2011b). Matsumura et al have shown that amphipatic DNA polymers inhibited HCV post-

It is clear that the immune response to viral infection plays a major role in the outcome of liver disease during HCV infection. To study the involvement of the innate immune system against viral infection, Walters et al., used the immunotolerant Alb-uPA/SCID mouse model to analyze transcriptome profiles of HCV infected versus non infected mice (Walters et al 2006). Globally, in the Alb-uPA/SCID mouse model, HCV infection activates the transcription of interferon-stimulated genes which are in particular implicated in establishing the innate immune response, and thus active in the inhibition of HCV replication. Moreover, and as previously shown in HCV-infected patients and HCV transgenic mice, these authors confirmed in the Alb-uPA/SCID mouse model the relationship between severe HCV infection and perturbation of lipid metabolism (Joyce et al

binding stage and thus blocked de novo infection (Matsumura et al 2009)

(Lutgehetmann et al 2011)

(Lutgehetmann et al 2010).

treatment for each patient (Kurbanov et al 2008).

The recent development of small mouse models for experimental HBV, HCV or Plasmodium falciparum infection has opened new perspectives for the evaluation of novel therapeutic and/or prophylactic compounds against these pathogens. These models are physiologically relevant, in that they are based on the transplantation of primary hepatocytes. However, to integrate humanized mouse technology into development process, the technology must be accessible, reproducible and at a reasonable cost. Indeed, both mouse models are relatively complicated to use, but they present the unquestionable advantage of being much less expensive and easier to maintain and breed than primates.

The present challenge is the construction of mice combining human immune and liver cells. Mice with humanized immune systems already represent the model of choice for various lymphotropic pathogens. The addition of human hepatic tissue holds promise for the study of hepatotropic pathogens. Indeed, this will help to understand how hepatotropic pathogens are detected by the immune system, why the majority of individuals fail to mount an effective response, the factors involved in chronic viral persistence versus resolution of infection. A recent report Washburn et al have developed a specific mouse model, humanized with human immune system and liver tissues (Washburn et al 2011). These mice generate a specific immune response against the HCV and seem to develop liver diseases.
