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Axes de recherche
- Interactions protéiques
- Approches thérapeutiques
- Biologie des systèmes
- Protein interactions
- Therapeutic approaches
- System biology
Hepatitis C virus (HCV) infection affects 3% of the population worldwide and is a serious cause of liver disease with infected individuals at risk of developing significant morbidity and mortality. HCV has been remarkably adept at escaping the human immune system leading to a persistent infection in the majority of acute cases. Chronic infection is typical, and the disease course although unpredictable can lead to liver failure, portal hypertension and hepatocellular carcinoma. The incidence of severe liver diseases, the fourth leading killer of Canadians by disease, kept increasing mainly due to chronic infection. The study of HCV biology and the characterization of viral proteins essential for replication have led to the introduction of novel class of HCV specific inhibitors. The identification of the NS3/4A protease inhibitor BILN 2061 (Lamarre et al., Nature 2003) has highlighted new therapeutic perspectives by validating the target in vivo and lead to the approval of first-in-class small-molecules in 2011 for the treatment of hepatitis C in combination with interferon and ribavirin. The novel therapy represents a paradigm shift in HCV therapy by offering improved viral cure rates and shorter treatment duration to many patient populations.
Using large scale proteomics approaches for HCV protein, our group focuses on identifying novel virus-host protein interactions and recruitment of cellular machineries during host infection in order to accomplish critical viral processes. We recently have identified the cellular cofactor Y-Box-Binding Protein-1, as an interacting partner of HCV NS3/4A protein and genomic RNA, which plays a crucial role in viral assembly. These studies will allow a better understanding of the pathophysiology of HCV infection with the aim of identifying novel therapeutic targets for the treatment of chronic diseases induced by the various HCV subtypes.
Our team exploits the power of RNAi technology at the genome scale to better understand antiviral host defences and to decipher virus-interfering mechanisms. We have conducted a lentivirus-based loss-of-function screen to identify regulators of the innate immune responses to virus infection. Many positive and negative potential regulators are under evaluation for which gene silencing significantly modulated virus-induced IFN-b expression and for which secondary screens yielded epistatic insight into their mode of action. These studies offer an opportunity to identify novel druggable pathways that would either modulate or circumvent immune evasion strategies with the aim of boosting the innate immune responses to virus infection as a new and challenging therapeutic field.
- Chatel-Chaix, L, Melançon, P, Racine, ME, Baril, M and Lamarre, D. (2011) Y-Box-Binding Protein-1 Interacts with Hepatitis C Virus NS3/4A and Influences the Equilibrium between Viral RNA Replication and Infectious Particle Production. J.Virol. 2011 Aug 17 PMID:21849455
- Jouan, L, Chatel-Chaix, L, Melançon, P, Rodrigue-Gervais, IG, Raymond, VA, Selliah, S, Bilodeau, M, Grandvaux, N and Lamarre D. (2011) Targeted impairment of innate antiviral responses in liver of chronic Hepatitis C patients. J. Hepat. 2011 Aug 8. PMID:21835140
- Jouan, L., Melançon, P., Rodrigue-Gervais, I.G., Raymond, V., Selliah, S., Boucher, G., Bilodeau, M., Grandvaux, N. and Lamarre, D. (2010) Distinct antiviral signaling pathways in primary human hepatocytes and their differential disruption by HCV NS3 protease. J. Hepat. 52:167
- Baril M, Racine ME, Penin F, Lamarre D. (2009) MAVS dimer is a crucial signaling component of innate immunity and the target of HCV NS3/4A protease. J Virol. 83(3):1299.
- Lamarre D, Anderson PC, Bailey M, Beaulieu P, et al (2003) An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 426:186.
- Rodrigue-Gervais, IG. and Lamarre, D. (2010) Les cellules dendritiques, acteurs immunitaires ou cibles du virus de l’hépatite C. Médecines et Sciences. Oct;26 (10):869.
- Chatel-Chaix L, Baril M and Lamarre, D. (2010) Hepatitis C Virus NS3/4A Protease Inhibitors: A Light at the End of the Tunnel. Viruses, 2, 1752.