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CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD 1 CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD Hepatitis C Virus Towards eradication of an oncogenic viral agent Prof. Jean-Michel Pawlotsky National Reference Center for Viral Hepatitis B, C and Delta, Department of Virology & INSERM U955 Hpital Henri Mondor Universit Paris-Est Crteil, France 1 Slide 2 CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD Hepatitis C Virus Infection 120-130 million individuals chronically infected worldwide 1 st cause of chronic liver disease and 1 st cause of hepatocellular carcinoma (HCC, primary liver cancer) in the industrialized world Mortality rate: >300,000/year Curable by therapy Pegylated IFN- and ribavirin Pegylated IFN- , ribavirin and a protease inhibitor (genotype 1) 2 Slide 3 CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD A Truly Translational Setting Clinical research unit Clinical trials Cohort studies Clinical virology lab National Reference Center for Viral Hepatitis B, C and D Basic research lab INSERM U955 3 Slide 4 CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD Clinical Group Christophe Hzode Anne Varaut Murielle Franois Marie Payet Isabelle Rivire Olivier Teston Isaac Ruiz Ariane Mallat Clinical Virology Group and National Reference Center For Viral Hepatitis B, C and D Stphane Chevaliez Dominique Challine Magali Bouvier-Alias, Jrmie Corneille Alexandre Soulier Nikolaos Gatselis Franoise Darthuy Charlne Prnom Drug screening and Resistance INSERM U955 Abdelhakim Ahmed-Belkacem Paul Ben Sadoun Coralie Pallier Christophe Rodriguez Nazim Ahnou Eva Hernandez Rozenn Brillet Liver Carcinogenesis INSERM U955 Herv Lerat Martin Higgs Philippe Chouteau Nicole Defer Thomas Decaens Muhamad Ahmad Maqbool Alexandre Florimond Mohamed Imache Aurore Gaudin 4 A Multidisciplinary Team Slide 5 CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD HCV Clinical Trials 0 1 2 3 4 5 6 7 8 2005 2006 2007 2008 2009 2010 Phase I Phase II Phase III Phase IV Number of clinical trials started 2005-2010: 586 patients included 5 Slide 6 CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD Viral genome extraction from serum RT PCR amplification emPCR Pyrosequencing PyroMute PyroDyn % of each mutations Analysis Data collection PyroClass PyroClass . PyroMute , PyroDyn , PyroLink are protected under IDDN Modeling of population growth Sequence quality filters PyroLink Linkages Classification of generated sequences (Rodriguez C. et al., AASLD 2010) New Virological Tools Next-Generation Sequencing 6 Slide 7 CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD HCV Resistance by UDPS (Chevaliez S. et al., EASL 2011) HCV RNA (Log 10 IU/mL) 0 2 4 6 8 Days of treatment % of mutations in the whole quasispecies % of variants in the quasispecies Days of therapyHCV RNA (Log 10 IU/mL) Viral populations 7 Slide 8 CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD Models for the Study of HCV-Induced Hepatocarcinogenesis 8 Liver tissues from HCV-infected patients with or without HCCs HCV-infected hepatoma cell lines harboring HCV replicons or infectious HCV strains HCV transgenic mouse model (FL-N/35) expressing the full HCV ORF* (*Lerat H, et al., Gastroenterology 2002;122::352-65) Slide 9 CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD HCV-Induced Hepatocarcinogenesis HCV protein expression CH 3 Mthylation Promoteur de Gadd45 ROS production DNA damage -catenin Promoteur de c-Myc c-Myc Impaired G2-M arrest Defective DNA damage repair Gadd45 Genomic instability Defective G1-S arrest Impaired DNA damage repair (Higgs M, et al., Cancer Res 2010;70:4901-11) 9 Slide 10 CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD HCV Drug Development Binding modes in HCV RNA-dependent RNA polymerase Thumb Pocket I of aurone inhibitors of HCV replication. (A) Compound 1 is involved in five hydrogen bonds: two with Arginine 503 (1.9 and 2.5 ), one with Glycine 493 (1.8 ) and two with Leucine 392 (2.0 and 2.0 ). (B) Compound 51 is involved in three hydrogen bonds: two with Arginine 503 (1.8 and 2.0 ) and one with Glycine 493 (2.2 ). The pictures were built using Pymol software (Haudecoeur R, Ahmed-Belkacem A, et al., J Med Chem 2011; in press) 10 Slide 11 CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD HCV Drug Development Fragment-Based Drug Design (FBDD) approach for small molecule cyclophylin inhibitors IC50 ( M) cyclophylin A EC50 ( M) HCV- 1b replicon compound A 0.40.14.50.8 compound B 3.31.41.40.2 compound C 0.81.21.00.3 (Ahmed-Belkacem A, et al., AASLD 2010) 11 Slide 12 CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD Perspectives 12 Vaccine Research Institute (VRI)