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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.

 

Current Lab members
Name Position Contact
Jerôme Gouttenoire Project leader jerome.gouttenoire@chuv.ch
Viet Loan Dao Thi PhD, Post-doc    viet-loan.dao-thi@chuv.ch
Huong Tran PhD student thi-lan-huong.tran@chuv.ch
Simon Meister Master student simon.meister@unil.ch
Rosa Castillo Technician rosa.castillo@chuv.ch

 

Full publication list (2013-09-01 185 Ko)

Selected publications


2013

1: Aouri M, Moradpour D, Cavassini M, Mercier, T, Buclin T, Csajka C, Telenti A, Rauch A, Decosterd LA.
    A multiplex LC MS/MS assay for the simultaneous therapeutic drug monitoring of ribavirin, boceprevir and telaprevir.
Antimicrob Agents Chemother 2013;57:3147-3158.
2: Bibert S, Roger T, Calandra T, Bochud M, Cerny A, Semmo N, Duong FHT, Gerlach T, Malinverni R, Moradpour D, Negro F, Müllhaupt B, Bochud P-Y, and the Swiss Hepatitis C Cohort Study.
    IL28B expression depends on a novel TT/-G polymorphism which improves HCV clearance prediction.
J Exp Med 2013;210:1109-1116.
3: Esser-Nobis K, Romero-Brey I, Ganten TM, Gouttenoire J, Harak C, Klein R, Schemmer P, Binder M, Schnitzler P, Moradpour D, Bartenschlager R, Polyak SJ, Stremmel W, Penin F, Eisenbach C, Lohmann V.
    Analysis of hepatitis C virus resistance to silibinin in vitro and in vivo points to a novel mechanism involving nonstructural protein 4B.
Hepatology 2013;57:953-963.
4: Lange CM, Bibert S, Dufour JF, Cellerai C, Cerny A, Heim MH, Kaiser L, Malinverni R, Müllhaupt B, Negro F, Semela D, Moradpour D, Kutalik Z, Bochud PY, and the Swiss Hepatitis C Cohort Study Group.
    Comparative genetic analyses point to HCP5 as susceptibility locus for HCV-associated hepatocellular carcinoma.
J Hepatol 2013;59:504-509.
5: Lange CM, Miki D, Ochi H, Nischalke H-D, Bojunga J, Bibert S, Morikawa K, Gouttenoire J, Cerny A, Dufour JF, Gorgievski-Hrisoho M, Heim MH, Malinverni R, Müllhaupt B, Negro F, Semela D, Kutalik Z, Müller T, Spengler U, Berg T, Chayama K, Moradpour D, Bochud PY, the Hiroshima Liver Study Group, and the Swiss Hepatitis C Cohort Study Group.
    Genetic analyses reveal a role for vitamin D insufficiency in HCV-associated hepatocellular carcinoma development.
PLoS One 2013;8:e64053.
6: Moradpour D and Penin F.
    Hepatitis C virus proteins: from structure to function.
Curr Top Microbiol Immunol 2013;369:113-142.
7: Morikawa K, Gouttenoire J, Hernandez C, Dao Thi VL, Tran HTL, Lange CM, Dill MT, Heim MH, Donzé O, Penin F, Quadroni M, Moradpour D.
    Quantitative proteomics identifies the membrane-associated peroxidase GPx8 as a cellular substrate of the hepatitis C virus NS3-4A protease.
Hepatology 2013, in press

2012

1: Bochud P-Y, Bibert S, Kutalik Z, Patin E, Guergnon J, Nalpas B, Goossens N, Kuske L, Müllhaupt B, Gerlach TJ, Heim MH, Moradpour D, Cerny A, Malinverni R, Regenass S, Dollenmaier G, Hirsch H, Martinetti G, Gorgievski M, Bourlière M, Poynard T, Theodorou I, Abel L, Pol S, Dufour J-F, Negro F, on behalf of the Swiss Hepatitis C Cohort Study Group.
    IL28B alleles associated with poor hepatitis C virus (HCV) clearance protect against inflammation and fibrosis in patients infected with non-1 HCV genotypes.
Hepatology 2012;55:384-394.
2: Lange CM, Bibert S, Kutalik Z, Burgisser P, Cerny A, Dufour JF, Geier A, Gerlach TJ, Heim MH, Malinverni R, Negro F, Regenass S, Badenhoop K, Bojunga J, Sarrazin C, Zeuzem S, Müller T, Berg T, Bochud PY, Moradpour D, and the Swiss Hepatitis C Cohort Study Group.
    A genetic validation study reveals a role of vitamin D metabolism in the response to interferon-a-based therapy of chronic hepatitis C.
PLoS One 2012;7:e40159.
3: Lange CM, Kutalik Z, Morikawa K, Bibert S, Cerny A, Dollenmaier G, Dufour J-F, Gerlach TJ, Heim MH, Malinverni R, Müllhaupt B, Negro F, Moradpour D*, Bochud PY*, and the Swiss Hepatitis C Cohort Study Group.
    Serum ferritin levels are associated with a distinct phenotype of chronic hepatitis C poorly responding to pegylated interferon-a and ribavirin therapy.
Hepatology 2012;55:1038-1047.
4: Patin E, Kutalik Z, Guergnon J, Bibert S, Nalpas B, Jouanguy E, Munteanu M, Bousquet L, Argiro L, Halfon P, Boland A, Müllhaupt B, Semela D, Dufour JF, Heim MH, Moradpour D, Cerny A, Malinverni R, Hirsch H, Martinetti G, Suppiah V, Stewart G, Booth DR, George J, Casanova JL, Bréchot C, Rice CM, Talal AH, Jacobson IM, Bourlière M, Theodorou I, Poynard T, Negro F, Pol S, Bochud PY, Abel L; Swiss Hepatitis C Cohort Study Group, International Hepatitis C Genetics Consortium; French ANRS HC EP 26 Genoscan Study Group.
    Genome-wide association study identifies variants associated with progression of liver fibrosis from HCV infection.
Gastroenterology 2012;143:1244-1252.
5: Quarato G, Scrima R, Gavillet B, Vuagniaux G, Moradpour D, Capitanio N, Piccoli C.
    The cyclophilin inhibitor alisporivir prevents hepatitis C virus-mediated mitochondrial dysfunction.
Hepatology 2012;55:1333-1343.
6: Swiss Association for the Study of the Liver.
    Treatment of chronic hepatitis C genotype 1 with triple therapy comprising telaprevir or boceprevir (Expert Opinion Statement).
Swiss Med Wkly 2012;142:w13516.
7: Wölk B, Trautwein C, Büchele B, Kersting N, Blum HE, Rammensee H-G, Cerny A, Stevanovic S, Moradpour D, Brass V.
    Identification of naturally processed hepatitis C virus-derived major histocompatibility complex class I ligands.
PLoS One 2012;7:e29286.

2011

1: Cai T, Dufour JF, Muellhaupt B, Gerlach T, Heim M, Moradpour D, Cerny A, Malinverni R, Kaddai V, Bochud M, Negro F, Bochud PY; On Behalf Of The Swiss Hepatitis C Cohort Study Group.
    Viral Genotype-Specific Role of PNPLA3, PPARG, MTTP and IL28B in Hepatitis C Virus-Associated Steatosis.
J Hepatol. 2011;55(3):529-535.
2: Lange CM, Moradpour D, Doehring A, Lehr HA, Müllhaupt B, Bibert S, Bochud PY, Antonino AT, Pascual M, Farnik H, Shi Y, Bechstein WO, Moench C, Hansmann ML, Sarrazin C, Lötsch J, Zeuzem S, Hofmann WP.
    Impact of donor and recipient IL28B rs12979860 genotypes on hepatitis C virus liver graft reinfection.
J Hepatol. 2011;55(2):322-327.
3: Morikawa K, Lange CM, Gouttenoire J, Meylan E, Brass V, Penin F, Moradpour D.
    Nonstructural protein 3-4A: the Swiss army knife of hepatitis C virus.
J Viral Hepat. 2011 May;18(5):305-15. doi: 10.1111/j.1365-2893.2011.01451.x.
4: Paul D, Romero-Brey I, Gouttenoire J, Stoitsova S, Krijnse-Locker J, Moradpour D, Bartenschlager R.
    NS4B self-interaction through conserved C-terminal elements is required for the establishment of functional hepatitis C virus replication complexes.
J Virol. 2011 Jul;85(14):6963-76.
5: Popescu CI, Callens N, Trinel D, Roingeard P, Moradpour D, Descamps V, Duverlie G, Penin F, Héliot L, Rouillé Y, Dubuisson J.
    NS2 protein of hepatitis C virus interacts with structural and non-structural proteins towards virus assembly.
PLoS Pathog. 2011 Feb 10;7(2):e1001278.

2010

1: Bellecave P, Sarasin-Filipowicz M, Donzé O, Kennel A, Gouttenoire J, Meylan E, Terracciano L, Tschopp J, Sarrazin C, Berg T, Moradpour D, Heim MH.
    Cleavage of mitochondrial antiviral signaling protein in the liver of patients with chronic hepatitis C correlates with a reduced activation of the endogenous interferon system.
Hepatology. 2010 Apr;51(4):1127-36.
2: Brass V, Gouttenoire J, Wahl A, Pal Z, Blum HE, Penin F, Moradpour D.
    Hepatitis C virus RNA replication requires a conserved structural motif within the transmembrane domain of the NS5B RNA-dependent RNA polymerase.
J Virol 2010;84:11580-11584.
3: Gouttenoire J, Penin F, Moradpour D.
    Hepatitis C virus nonstructural protein 4B: a journey into unexplored territory.
Rev Med Virol. 2010 Mar;20(2):117-29.
4: Gouttenoire J, Roingeard P, Penin F, Moradpour D.
    Aminoterminal amphipathic alpha-helix AH2 is a major determinant for the oligomerization of hepatitis C virus nonstructural protein 4B.
J Virol 2010;84:12529-12537.
5: Jirasko V, Montserret R, Lee JY, Gouttenoire J, Moradpour D, Penin F, Bartenschlager R.
    Structural and functional studies of nonstructural protein 2 of the hepatitis C virus reveal its key role as organizer of virion assembly
PLoS Pathog. 2010 Dec 16;6(12):e1001233.
6: Rauch A, Kutalik Z, Descombes P, Cai T, Di Iulio J, Mueller T, Bochud M, Battegay M, Bernasconi E, Borovicka J, Colombo S, Cerny A, Dufour JF, Furrer H, Günthard HF, Heim M, Hirschel B, Malinverni R, Moradpour D, Müllhaupt B, Witteck A, Beckmann JS, Berg T, Bergmann S, Negro F, Telenti A, Bochud PY; Swiss Hepatitis C Cohort Study; Swiss HIV Cohort Study.
    Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study.
Gastroenterology. 2010 Apr;138(4):1338-45, 1345.e1-7.
7: Ripoli M, D'Aprile A, Quarato G, Sarasin-Filipowicz M, Gouttenoire J, Scrima R, Cela O, Boffoli D, Heim MH, Moradpour D, Capitanio N, Piccoli C.
    Hepatitis C virus-linked mitochondrial dysfunction promotes hypoxia-inducible factor 1 alpha-mediated glycolytic adaptation.
J Virol. 2010 Jan;84(1):647-60.

2009

1: Bellecave P, Gouttenoire J, Gajer M, Brass V, Koutsoudakis G, Blum HE, Bartenschlager R, Nassal M, Moradpour D.
    Hepatitis B and C virus coinfection: a novel model system reveals the absence of direct viral interference.
Hepatology 2009;50:46-55.
2: Brass V, and Moradpour D.
    New insights into hepatitis B and C virus co-infection.
J Hepatol. 2009 Sep;51(3):446-57.
3: Gouttenoire J, Castet V, Montserret R, Arora N, Raussens V, Ruysschaert JM, Diesis E, Blum HE, Penin F, Moradpour D.
    Identification of a novel determinant for membrane association in hepatitis C virus nonstructural protein 4B.
J Virol. 2009;83:6257-6268.
4: Gouttenoire J, Montserret R, Kennel A, Penin F, Moradpour D.
    An amphipathic alpha-helix at the C terminus of hepatitis C virus nonstructural protein 4B mediates membrane association.
J Virol. 2009; 83:11378-11384.
5: Wölk B, and Moradpour D.
    The promise of advanced imaging techniques for the detection of hepatitis C virus antigens in the infected liver.
Gastroenterology 2009; 137:1214-1218.

2008

1: Bellecave P, and Moradpour D.
    A fresh look at interferon-alpha signaling and treatment outcomes in chronic hepatitis C.
Hepatology 2008;48:1330-1333.
2: Brass V, Berke JM, Montserret R, Blum HE, Penin F, Moradpour D.
    Structural determinants for membrane association and dynamic organization of the hepatitis C virus NS3-4A complex.
Proc Natl Acad Sci USA 2008;105:14545-14550.
3: Wölk B, Büchele B, Moradpour D, Rice CM.
    A dynamic view of hepatitis C virus replication complexes.
J Virol. 2008;82:10519-10531.

2007

1: Brass V, Pal Z, Sapay N, Deléage G, Blum HE, Penin F, Moradpour D.
    Conserved determinants for membrane association of nonstructural protein 5A from hepatitis C virus and related viruses.
J Virol. 2007;81:2745-2757.
2: Moradpour D, Penin F, Rice CM.
    Replication of hepatitis C virus.
Nat Rev Microbiol. 2007;5:453-463.

2006

1: Bellecave P, and Moradpour D.
    A picture says more than a thousand words: structural insights into hepatitis C virus translation initiation.
Hepatology 2006;44:1687-1690.
2: Combet C, Charavay C, Grando D, Crisan D, Lopez J, Garnier N, Geourjon C, Bettler E, Hulo C, Bairoch A, Bartenschlager R, Diepolder H, Moradpour D, Pawlotsky J-M, Rice DM, Trépo C, Penin F, Deléage G.
    euHCVdb: the European Hepatitis C Virus Database
Nucleic Acids Res. 2007;35:D363-366
3: Gouttenoire J, Moradpour D, Penin F.
    Surprises from the three-dimensional structure of the hepatitis C virus NS2-3 protease.
Hepatology 2006;44:1690-1693.
4: Sapay N, Montserret R, Chipot C, Brass V, Moradpour D, Deléage G, Penin F.
    NMR structure and molecular dynamics of the in-plane membrane anchor domain of nonstructural protein 5A from bovine viral diarrhea virus.
Biochemistry 2006;45:2221-2233.

2005

1: Berke JM, and Moradpour D.
    Hepatitis C virus comes full circle: production of recombinant infectious virus in tissue culture.
Hepatology 2005;42:1264-1269.
2: Gosert R, Jendrsczok W, Berke JM, Brass V, Blum HE, Moradpour D.
    Characterization of nonstructural protein membrane anchor deletion mutants expressed in the context of the hepatitis C virus polyprotein.
J Virol. 2005;79;7911-7917.
3: Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, Tschopp J.
    Cardif is a novel adaptor protein in RIG-I-mediated antiviral responses targeted by hepatitis C virus.
Nature 2005;437:1167-1172.
4: Moradpour D, Brass V, Penin F.
    Function follows form: the structure of the N-terminal domain of HCV NS5A.
Hepatology 2005;42:732-735.
5: Wölk B, Gremion C, Ivashkina N, Engler OB, Grabscheid B, Bieck E, Blum HE, Cerny A, Moradpour D.
    Stable human lymphoblastoid cell lines constitutively expressing hepatitis C virus proteins.
J Gen Virol. 2005;86:1737-1746.

2004

1: Moradpour D, Brass V, Bieck E, Friebe P, Gosert R, Blum HE, Bartenschlager R, Penin F, Lohmann V.
    Membrane association of the RNA-dependent RNA polymerase is essential for hepatitis C virus RNA replication.
J Virol. 2004;78:13278-13284.
2: Moradpour D, Evans MJ, Gosert R, Yuan ZH, Blum HE, Goff SP, Lindenbach BD, Rice CM.
    Insertion of green fluorescent protein into nonstructural protein 5A allows direct visualization of functional hepatitis C virus replication complexes.
J Virol. 2004;78:7400-7409.
3: Penin F, Brass V, Appel N, Ramboarina S, Montserret R, Ficheux D, Blum HE, Bartenschlager R, Moradpour D.
    Structure and function of the membrane anchor domain of hepatitis C virus nonstructural protein 5A.
J Biol Chem. 2004;279:40835-40843.

2003

1: Gosert R, Egger D, Lohmann V, Bartenschlager R, Blum HE, Bienz K, Moradpour D.
    Identification of the hepatitis C virus RNA replication complex in Huh-7 cells harboring subgenomic replicons.
J Virol. 2003;77:5487-5492.

2002

1: Brass V, Bieck E, Montserret R, Wölk B, Hellings JA, Blum HE, Penin F, Moradpour D.
    An aminoterminal amphipathic alpha-helix mediates membrane association of the hepatitis C virus nonstructural protein 5A.
J Biol Chem. 2002;277:8130-8139.
2: Egger D, Wölk B, Gosert R, Bianchi L, Blum HE, Moradpour D, Bienz K.
    Expression of hepatitis C virus proteins induces distinct membrane alterations including a candidate viral replication complex.
J Virol. 2002;76:5974-5984.
3: Ivashkina N, Wölk B, Lohmann V, Bartenschlager R, Blum HE, Penin F, Moradpour D.
    The hepatitis C virus RNA-dependent RNA polymerase membrane insertion sequence is a transmembrane segment.
J Virol. 2002;76:13088-13093.
4: Moradpour D, Bieck E, Hügle T, Wels W, Wu JZ, Hong Z, Blum HE, Bartenschlager R.
    Functional properties of a monoclonal antibody inhibiting the hepatitis C virus RNA-dependent RNA polymerase.
J Biol Chem. 2002;277:593-601.


Last Update on 19.09.2013 - Publication credits - Legal information