|Pathogenesis of hepatitis B virus - INSERM U 845|
|HEAD||Dr Marie-Louise MICHEL / email@example.com|
|MEMBERS||Dr. Marie-Louise MICHEL/ Dr. Maryline MANCINI-BOURGINE/ Dr. Ren ZHU, CDD INSERM/ Dr. Sarah DION : Dr. Florence BAYARD/ Ophélie GODON/ Ana de CASAS
Dr. Dina KREMSDORF/ Dr. Patrick SOUSSAN/ François REDELSBERGER/ Yvan QUETIER/ Nicolas BREZILLON/ Bouchra LEKBABY/ Hélène MASSINET/ Mary WEISS
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 370 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 cirrhosis and 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 try to 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. To study T cell responses to HBV proteins we have obtained a novel animal model for chronic HBV-carriers with “humanized” T cell responses. These 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 candidates tested in mice transgenic for human MHC molecules 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. A proof of concept study (phase I trial) of therapeutic DNA-based vaccination for HBV chronic infection was conducted in patients suffering from chronic hepatitis B. Results showed good tolerance to the vaccine and activation of adaptive immunity and of a particular subset of NK cells. A phase II multi-centric trial combining antiviral agents and DNA-based vaccine therapy is ongoing. In this trial we analyze the immune response activated by the DNA vaccine and try to determine whether the response can be linked to control of viral replication after discontinuation of treatment (Dr. H. Fontaine, AP-HP, Hopital Cochin, PI; ANRS is the sponsor of the study).
As an alternative approach to vaccine therapy, we are using the HBV genome as a gene therapy vector to deliver foreign antigenic determinants to HBV-infected liver cells and to attract functionally active T cells to liver. We expect that these functional T cells would control HBV multiplication.
Keywords: Hepatitis B, liver disease, murine model, T-cell response, NK cells, vaccine, immuno-therapy, gene therapy
MANCINI-BOURGINE M, FONTAINE H, BRECHOT C, POL S, MICHEL ML. Immunogenicity of a hepatitis B DNA vaccine administered to chronic HBV carriers. Vaccine. 2006, 24 : 4482-4489. PMID: 16310901
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. PMID: 17465004
Mancini-Bourgine M, Bayard F, Soussan P, Deng Q, Lone YC, Kremsdorf D, Michel ML. 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. PMID: 17360751
DENG Q, MANCINI-BOURGINE M, ZHANG X, CUMONT MC, ZHU R, LONE YC, MICHEL ML. Hepatitis B virus as a gene delivery vector activating foreign antigenic T cell response that abrogates viral expression in mouse models. Hepatology. 2009 ; 50(5):1380-91. PMID: 19821533
SCOTT-ALGARA D, MANCINI-BOURGINE M, FONTAINE H, POL S, MICHEL ML. Changes to the natural killer cell repertoire after therapeutic hepatitis B DNA vaccination. PLOS One Research Article, published 18 Jan 2010. doi:10.1371/journal.pone.0008761
Activity Reports 2009 - Institut Pasteur
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