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Hepatitis C Virus Towards eradication of an oncogenic viral agent

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Presentation on theme: "Hepatitis C Virus Towards eradication of an oncogenic viral agent"— Presentation transcript:

1 Hepatitis C Virus Towards eradication of an oncogenic viral agent
1 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 Hôpital Henri Mondor Université Paris-Est Créteil, France CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD

2 Hepatitis C Virus Infection
2 million individuals chronically infected worldwide 1st cause of chronic liver disease and 1st cause of hepatocellular carcinoma (HCC, primary liver cancer) in the industrialized world Mortality rate: >300,000/year Curable by therapy Pegylated IFN-a and ribavirin Pegylated IFN-a, ribavirin and a protease inhibitor (genotype 1)

3 A Truly Translational Setting
3 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

4 A Multidisciplinary Team
4 Clinical Group Christophe Hézode Anne Varaut Murielle François Marie Payet Isabelle Rivière Olivier Teston Isaac Ruiz Ariane Mallat Drug screening and Resistance INSERM U955 Abdelhakim Ahmed-Belkacem Paul Ben Sadoun Coralie Pallier Christophe Rodriguez Nazim Ahnou Eva Hernandez Rozenn Brillet Clinical Virology Group and National Reference Center For Viral Hepatitis B, C and D Stéphane Chevaliez Dominique Challine Magali Bouvier-Alias, Jérémie Corneille Alexandre Soulier Nikolaos Gatselis Françoise Darthuy Charlène Prénom Liver Carcinogenesis INSERM U955 Hervé Lerat Martin Higgs Philippe Chouteau Nicole Defer Thomas Decaens Muhamad Ahmad Maqbool Alexandre Florimond Mohamed Imache Aurore Gaudin

5 HCV Clinical Trials 2005-2010: 586 patients included
7 6 Phase I Phase II Phase III Phase IV 5 Number of clinical trials started 4 3 2 1

6 New Virological Tools Next-Generation Sequencing
6 Data collection Viral genome extraction from serum RT PCR amplification emPCR Pyrosequencing Analysis PyroClass® PyroMute® PyroDyn® PyroLink® % of each mutations Modeling of population growth Classification of generated sequences Sequence quality filters Linkages PyroClass©. PyroMute©, PyroDyn©, PyroLink© are protected under IDDN (Rodriguez C. et al., AASLD 2010)

7 HCV Resistance by UDPS 7 8 % of variants in the quasispecies
% of mutations in the whole quasispecies 6 HCV RNA (Log10 IU/mL) 4 HCV RNA (Log10 IU/mL) 2 Days of treatment Days of therapy Viral populations (Chevaliez S. et al., EASL 2011)

8 Models for the Study of HCV-Induced Hepatocarcinogenesis
8 Models for the Study of HCV-Induced Hepatocarcinogenesis 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)

9 HCV-Induced Hepatocarcinogenesis
9 HCV protein expression Promoteur de Gadd45b CH3 CH3 b-catenin Méthylation ROS production Promoteur de c-Myc Gadd45b c-Myc DNA damage Defective G1-S arrest Impaired DNA damage repair Genomic instability Impaired G2-M arrest Defective DNA damage repair (Higgs M, et al., Cancer Res 2010;70: )

10 HCV Drug Development 10 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 Å and 2.5 Å), one with Glycine 493 (1.8 Å) and two with Leucine 392 (2.0 Å and 2.0 Å). (B) Compound 51 is involved in three hydrogen bonds: two with Arginine 503 (1.8 Å and 2.0 Å) and one with Glycine 493 (2.2 Å). The pictures were built using Pymol software (Haudecoeur R, Ahmed-Belkacem A, et al., J Med Chem 2011; in press)

11 HCV Drug Development Fragment-Based Drug Design
11 Fragment-Based Drug Design (FBDD) approach for small molecule cyclophylin inhibitors IC50 (mM) cyclophylin A EC50 (mM) HCV-1b replicon compound A 0.4±0.1 4.5±0.8 compound B 3.3±1.4 1.4±0.2 compound C 0.8±1.2 1.0±0.3 (Ahmed-Belkacem A, et al., AASLD 2010)

12 Vaccine Research Institute (VRI)
Perspectives 12 Vaccine Research Institute (VRI)


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