Pathogenesis of hepatitis B virus - INSERM U 845  


  HEADDr Marie-Louise MICHEL / maloum@pasteur.fr
  MEMBERSDr. Marie-Louise MICHEL, INSERM / Dr. Maryline MANCINI-BOURGINE, Institut Pasteur / Dr. Silvina MALMASSAR Institut Pasteur / Dr. Qiang DENG, CDD, Institut Pasteur
Dr. Ren ZHU, Institut Pasteur Shanghaï / Florence BAYARD, CNRS / Ana de CASAS, assistant, Institut Pasteur


  Annual Report

Despite the existence of safe and efficient vaccines for more than twenty years, hepatitis B remains a public health problem of worldwide importance. It is currently estimated that 350 million people are chronic carriers of hepatitis B virus (HBV), and hepatitis B is held responsible for 1.2 million deaths each year. Furthermore, these chronic carriers represent an important reservoir for viral dissemination. Chronic HBV infection is a major risk factor for the development of hepatocellular carcinoma. It is clear that the immune mechanisms associated with the antiviral response play a major role in disease outcome. The aim of our research programme is to gain a clearer understanding of the physiopathology and immunopathology of chronic liver disease caused by HBV infection and thus to develop therapeutic approaches aimed at controlling viral replication, improving histologic lesions of liver and ultimately to provide a cure for this disease.

Although HBV is not considered as a cytopathic virus, some arguments suggest that viral proteins may also participate directly in liver disease. Our work is in favour of a direct effect of the hepatitis B X protein (HBx) and of the hepatitis B splice-generated protein (HBSP) in the evolution of the hepatic pathogenesis associated to HBV infection. We study the cellular and molecular mechanisms by which these two proteins participate in the liver pathogenesis during viral infection. We also analyse the T-cell immune responses specific for HBSP, HBx and other HBV proteins in patients suffering from chronic infection and correlate them with disease evolution.

The narrow host specificity of HBV and the deficit in simple models of in vitro or in vivo infection remain a considerable handicap for the knowledge of the mechanisms implied in the viral pathogenesis. We have developed a mouse model engrafted with human hepatocytes allowing the reproduction of the complete replication cycle of HBV infectionand the study of new therapeutic drugs others than those which target viral polymerase.

To study T cell responses to HBV proteins we have now obtained a novel animal model for chronic HBV-carriers with “humanized” T cell responses. These triple transgenic mice express human MHC class I (HLA-A2) and MHC class II (HLA-DRB1*01) molecules and are devoid of endogenous murine class I and class II molecules. In this mouse lineage, the HBV transgene codes for the 3 envelope proteins that are expressed in the liver. Our novel animal model will be useful to evaluate vaccine candidates or immunomodulatory drugs for their ability to induce cellular immune responses with functional properties.

In the absence of any antiviral therapies that are fully effective in the long term, we are developing new strategies to enable a sustained control of infection in chronic HBV carriers. These are based on active immunotherapy aimed at achieving the control of viral infection by the immune system. Definition of HBV epitopic sequences recognized by T cells during HBV infection and design of vaccine candidate tested in mice transgenic for human MHC molecules will allow implementing innovative therapeutic vaccine trials in patients suffering from HBV chronic infection. To this end, we collaborate with physicians from various hospitals to push these projects further and this has led to a phase I trial of vaccine therapy administered to chronic HBV carriers.

Keywords: Hepatitis B, liver disease, murine model, T-cell response, vaccine, immunotherapy



  Publications

  1. Bourgine–Mancini M, Fontaine H, Scott-Algara D, Pol S, Bréchot C, Michel ML. 2004 Induction or expansion of T-cell responses by a hepatitis B DNA vaccine administered to chronic HBV carriers. Hepatology. 2004. 40: 874-882.

  2. Peltekian C, Gordien E, Garreau F, Meas-Yedid V, Soussan P, Chaix M-L, Olivo-Marin J-C, BrEchot C, Kremsdorf D. 2005 In vivo human MxA protein moderately down-regulate hepatitis B virus replication in female transgenic mice. J. Hepatol, 2005;43(6):965-72.

  3. Morosan S, Hez-Deroubaix S, Lunel F, Renia L, Giannini C, Van Rooijen N, Battaglia S, Blanc C, Eling W, Sauerwein R, Hannoun L, Belghiti J, Brechot C, Kremsdorf D, Druilhe P. 2006. Liver-stage development of Plasmodium falciparum, in a humanized mouse model. J Infect Dis. 2006, 193 : 996-1004.

  4. Malmassari SL, Deng Q, Fontaine H, Houitte D, Rimlinger F, Thiers V, Maillere B, Pol S, Michel ML. 2007 Impact of hepatitis B virus basic core promoter mutations on T cell response to an immunodominant HBx-derived epitope. Hepatology. 2007, 45 : 1199-1209.

  5. Mancini-Bourgine M, Bayard F, Soussan P, Deng Q, Lone YC, Kremsdorf D, Michel ML. 2007 Hepatitis B virus splice-generated protein induces T-cell responses in HLA-transgenic mice and hepatitis B virus-infected patients. J Virol. 2007, 81 : 4963-4972.





Activity Reports 2007 - Institut Pasteur
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