Darius Moradpour Lab

Darius Moradpour, MD, Professor of Medicine
Chief of the Division of Gastroenterology and Hepatology
Centre Hospitalier Universitaire Vaudois
University of Lausanne
Rue du Bugnon 44
CH-1011 Lausanne
++41(0)21-3144723 (direct line); ++41(0)21-3144714 (secretary); ++41(0)21-3144718 (Fax)
darius.moradpour@chuv.ch

Research topics

Molecular virology and pathogenesis of hepatitis C

Hepatitis C virus (HCV) infection is a leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma worldwide. Research in our laboratory concentrates on the molecular virology and pathogenesis of hepatitis C, including the development of new model systems, the investigation of structural and functional properties of HCV proteins, analyses of interactions of these proteins with cellular proteins and functional pathways, and studies on the immune response of patients with hepatitis C.

HCV life cycle. a) Virus binding and internalization, b) cytoplasmic release and uncoating, c) IRES-mediated translation and polyprotein processing, d) RNA replication, e) packaging and assembly, f) virion maturation and release. The topology of HCV structural and nonstructural proteins at the endoplasmic reticulum membrane is shown schematically. HCV RNA replication occurs in a specific membrane alteration, the membranous web. Note that IRES-mediated translation and polyprotein processing as well as membranous web formation and RNA replication, illustrated here as separate steps for simplicity, may occur in a tightly coupled fashion (from Moradpour D. et al. Nat. Rev. Microbiol. 2007;5:453-463.)

Structure and function of the HCV replication complex

Formation of a replication complex, composed of viral proteins, replicating viral RNA, and altered cellular membranes, is a hallmark of all positive-strand RNA viruses. In this context, we have identified a specific membrane alteration, designated as membranous web, that harbors the HCV replication complex. More recently, we have developed a replicon system that allows the direct visualization of such complexes in living cells. In addition, we have identified and characterized the determinants for membrane association of the HCV nonstructural proteins involved in viral RNA replication. Our recent structural and functional data indicate that these segments represent highly specialized structures that are involved in specific protein-protein interactions essential for the formation of a functional replication complex. Such interactions as well as other viral and cellular determinants involved in the formation of a functional replication complex are currently being investigated by biochemical, cell biological, genetic and advanced imaging techniques. Progress in this direction should enhance our understanding of the functional architecture of the HCV replication complex and may contribute to the development of novel antiviral strategies against hepatitis C. These studies are supported by the Swiss National Science Foundation, the Novartis Foundation, and the European Commission.

Studies on HBV-HCV coinfection

A second line of research focuses on interactions between HCV and hepatitis B virus (HBV). Disease progression in chronic hepatitis C is highly variable and depends on a number of factors, including coinfection with HBV. However, the molecular aspects of HBV-HCV coinfection are poorly understood because of the lack of a suitable model system. We have recently established a cell culture system that allows the simultaneous replication and production of infectious HBV and HCV. This system is currently being further developed and exploited. The results of these studies should yield novel insights into the natural history and clinical management of hepatitis C and HBV-HCV coinfection. These efforts are supported by the Swiss Cancer League and the Leenaards Foundation.

Interference of HCV with innate antiviral pathways

HCV has evolved various strategies to counteract the host immune response and to establish persistent infection. Recent work has identified the HCV NS3-4A serine protease as a key viral protein blocking innate immune sensing pathways. NS3-4A cleaves and inactivates the essential adaptor molecule Cardif in the RIG-I viral RNA-sensing pathway, thereby blocking interferon production. We are currently extending these studies in liver biopsies from patients with hepatitis C to determine the relationship between Cardif cleavage in vivo and HCV genotype and viremia as well as hepatitis C natural history and treatment outcome. In addition, we have initiated a proteomics-based approach to identify novel cellular targets of the HCV NS3-4A protease. These studies may reveal novel insights into the pathogenesis of hepatitis C and may provide clinically useful markers of disease activity and predictors of treatment response. They are supported by the Swiss National Science Foundation and the Désirée and Niels Yde Foundation.

Selected publications