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.
Our group focuses on identifying novel HCV-host protein interactions using large scale proteomics approaches for HCV proteins and recruitment of cellular machineries during host infection in order to accomplish critical viral processes. We recently have identified many cellular host factors including Y-Box-Binding Protein-1 as an interacting partner of HCV NS3/4A protein and genomic RNA that plays a crucial role in viral life cycle assembly.
Although HCV infection is one of the most widespread chronic infectious diseases, its natural pathogenesis and the mechanisms pertaining to viral persistence are rather still poorly understood. We recently reported a subversion of the hepatocyte-intrinsic innate immunity and impairment in the expression of early antiviral genes in tissues of patients with chronic hepatitis C end-stage liver disease. We demonstrated that the ectopic expression of the HCV NS3/4A protease is able to abrogate the antiviral effector responses in human primary hepatocytes by cleaving the adaptor CARDIF, a key component of the host antiviral signal propagation. We also reported the first study of an HCV RNA genome-dependent loss-of-function in the pathogen danger sensing pathway of blood myeloid dendritic cells, restorable with protease inhibitor BILN 2061, which translated into a decreased polyfunctional capacities of HCV-specific T cells in infected patients.
Our team exploits the power of RNAi technology at the genome scale to better understand antiviral host defenses 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- expression and for which secondary screens yielded epistatic insight into their mode of action. This research will lead to a better understanding of the host antiviral responses and interfering mechanisms employed by viruses to suppress host signaling propagation mediated by pattern recognition receptors. It should also lead to the development of therapeutic interventions aimed at modulating viral pathogenesis and at developing immunomodulatory pan-therapies for a broad spectrum of virus infections and of immune-mediated or auto-immune diseases.