HEADDr MEURS Eliane / emeurs@pasteur.fr
Dr MAILLARD Patrick / NICOLA Noémie / VILASCO Myriam / Dr VITOUR Damien / WALIC Marine

  Annual Report

We investigate the interaction of hepatitis C virus (HCV) with its target cell and with the host immune response, in order to develop new approaches to inhibit its replication and propagation. For this, we are characterizing mechanisms of HCV cell entry and interaction with the Interferon (IFN) inducing pathway.

Mechanisms of HCV cellular entry, its interaction with “scavenger” receptor (SRB1) lipoproteins and lipoprotein lipase (group A.Budkowska). There are several candidate-receptors for HCV based on their reactivity with the viral E2 envelope glycoprotein but their role in the cell infection with natural HCV circulating in the serum of patients remains to be determined. Natural HCV is associated with different classes of lipoproteins (LDL, VLDL, HDL) and could use lipoprotein receptors for cell entry. We demonstrated that the human « scavenger » receptor SR-BI/Cla1, which interacts with HDL, LDL, VLDL and facilitates cholesterol efflux to these lipoproteins can also bind and internalize natural HCV, in a process independent of E2 envelope glycoprotein but mediated by lipoproteins (mainly VLDL) associated to the virus. Our results suggest that cell infection with natural HCV can be mediated by apoB lipoproteins (VLDL et LDL) associated to the virus and lipoprotein receptors on the hepatocyte: SR-BI/Cla1 and LDL-R. This mechanism would permit cell infection in the presence of neutralizing antibodies and could help to escape the host immune responses. We showed equally that the cellular uptake of natural HCV into hepatic cells is mediated by lipoprotein lipase (LPL) after formation of a bridge between virus associated lipoproteins and cell surface heparan sulfate proteoglycans Our findings suggest the existence of a new mechanism for HCV cellular entry involving virus associated apo-B containing lipoproteins and dimeric and catalytically active lipoprotein lipase, analogical to the hepatic uptake of lipoproteins (Figure).

The role of the Interferon (IFN) inducing pathway in the control of HCV infection (groupe E.Meurs). Soon after HCV’s cell entry, some motifs from its RNA genome trigger two cellular pathways: the endosomal receptor TLR3 coupled to its cytosolic adapter TRIF and the cytosolic RNA helicase RIG-I coupled to the mitochondria-bound adapter Cardif. Both lead to induction of IFN and of the innate immune response, through activation of the TBK1/IKKε kinases. However, the HCV NS3/4A protease can cleave both TRIF and Cardif. This abrogates IFN induction and allows the virus to escape the host’s resistance (Figure). We showed that expression of RIG-I and of IKKε, but not of TBK1, were strongly inhibited in liver biopsies from HCV-infected patients. This demonstrates that, in vivo, HCV propagates preferentially from cells impaired in IFN induction. By overexpressing IKKε in an HCV replicon model, we showed that it could inhibit HCV replication and that its transcriptome profile contains genes involved in translational control/apoptosis. Upon viral infection, IKKε activates after recruitment to Cardif. We recently identified a cellular protein involved in proliferation which prevents the Cardif/IKKε association, thus abrogating IFN induction. This now leads to the design of novel inhibitors aimed at protecting the Cardif/IKKε association and innate immune response.


Figure .Binding of HCV to its target cell via lipoproteins , entry and induction of IFN through activation of the TLR3/TRIF and RIG-I/Cardif pathways


Publications 2006 of the unit on Pasteur's references database

Activity Reports 2006 - Institut Pasteur
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