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Ivan Hirsch Institut de Cancérologie de Marseille, UMR 599 INSERM Institut Paoli-Calmettes Université de la Méditerranée 27, boulevard Lei Roure 13009.

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Presentation on theme: "Ivan Hirsch Institut de Cancérologie de Marseille, UMR 599 INSERM Institut Paoli-Calmettes Université de la Méditerranée 27, boulevard Lei Roure 13009."— Presentation transcript:

1 Ivan Hirsch Institut de Cancérologie de Marseille, UMR 599 INSERM Institut Paoli-Calmettes Université de la Méditerranée 27, boulevard Lei Roure MARSEILLE (France) Phone : +33-(0) Fax : +33-(0) Web site: Hépatite C et le système immunitaire Réplication virale Infection chronique Immunité innée Interférons du type I Cellules dendritiques plasmacytoïdes Cancer hépatocellulaire

2 Familles de virus à ARN humains et animaux

3 Familles de virus à ADN humains et animaux

4 Classification de virus (David Baltimore) +ARNm +ARN -ARN ±ARN-ARN +ARN-ADN±ADN +ADN rétrovirus HBV HAV HCV HEV

5 HCV target cells Dendritic cell Hepatocytes Lymphocytes B T Kupffer cell Failure to develop general and efficient permissive system for HCV replication in vitro

6 Virus de la hépatite C Virus à lARN + : Organisation du génome C E1-E2 Core Envelope glycoprotein Serine protease Protéines non-structuralesstructurales polyprotéine ARNm Poliomyélite Hépatite A, C Fièvre jaune domaines protéolytiques Impairment of production of IFN- Resistance to IFN-

7 Virus de la hépatite A Virus à lARN + : Organisation du génome

8 HAV, HCV - Virus à ARN + : cycle viral Hépatocyte Vaccines Monoclonal antibodies Membrane-association Intervention? NS2-NS3 and NS3-4A Protease inhibitors P7 Inhibitors? Single-stranded RNA and core (nucleocapsid) HCV CD81 E1/E2 LDLR replicase Receptor inhibitors NS3-helicase and NS5B-Polymerase inhibitors Ribavirin IFN -

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10 HCV therapy IFN-, ribavirin clinical resolution in 50% cases (genotype dependent) Protease inhibitors (phase 3) Polymerase inhibitors (phase 3)

11 Mécanismes de le restriction virale Virus à lARN : interféron

12 Mechanism of viral detection endosome nucleus MyD88 sensors dsRNA-TLR3 TLR7-ssRNA TLR8-ssRNA TLR9-dsDNA TRIF nucleus RIG-1 MDA-5 CARD helicase MAVS, IPS-1 VISA, CARDIF TLR (Toll-like receptor) CARD-helicases mitochondria RIG-I, retionic acid induced gene MDA-5, melanoma differentiating antigen CARD, caspase activation and recruitment domain CARDIF, CARD adaptor inducing IFN- MAVS, mitochondrial anti-viral signaling IPS-1, interferon- promoter stimulator adaptators

13 CARDIF TBK-1 IKK- RIG-1 MDA-5 helicases IRF3 NF- B AP-1 CARD nucleus IFN- NS3/4A replication IFN- HCV infection: delicate equilibrium between virus replication and IFN- / interference RIG-1-dependent mechanism of IFN- induction in hepatocytes pDC Anti-HCV therapy CD81 LDLR

14 Virus de la hépatite B Hepadna virus : Organisation du génome Polymerase small middle Large Core X (+) strand (-) strand

15 Cycle réplicatif du virus de lhépatite B (HBV)

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18 Mécanismes de la restriction virale Virus avec transcriptase inverse : APOBEC3G

19 Pathogenèse

20 Pathogenèse de linfection par le virus de la hépatite A

21 Pathogenèse de linfection par le virus de la hépatite B et C

22 Pathogenèse de linfection par le virus de la hépatite B et C acute hepatitis Time line of cumulative morbidity during chronic infection inactive hepatitis hepatitis cirrhosis HCC Chronicité 0% HAV 10% HBV 70% HCV

23 Virus et cancer

24 HCV/HBV pathogenesis Oncogene (2003), TM Block, R. Jordan Death due to the five most common cancer diagnoses in 2001

25 Viral etiology of HCC Oncogene (2003), TM Block, R. Jordan

26 Requirements for viral replication Strict intracellular parasites proliferating cell Permanent activation of cell signal transduction Disruption of regulation of: - cell cycle progression - cell death, apoptosis - senescence, telomerase Immune evasion (Alessandro Moretta)

27 Virus and Cancer 20% of human cancer Malignancy is not required for virus propagation Malignancy is a side effect of infection or host response Viruses are unwitting initiators of oncogenesis Unfortunate outcome for the host

28 Oncogene transducing retroviruses paradigm Permanent activation of cell signal transduction Seminal role in the cancerogenesis research Protein kinases src, abl, mos, raf Tyrosine kinase growth-factor receptors erb-B, sea, kit, ros Hormone receptors erbA G proteins H-ras, K-ras Nuclear proteins jun, fos, myc, myb, ets, rel, ski LTR gagpolenv oncogene

29 Oncogenic viruses and cancer Viral familyassociated human cancer RNA viruses FlaviviridaeHCVhepatocellular carcinoma cytoplasma RetroviridaeHTLVT cell leukemia HIVcarcinomas, lymphomas DNA viruses HepadnaviridaeHBVhepatocellular carcinoma PapillomaviridaeHPV16,18 cervical carcinoma HerpesviridaeEBVBL, NPC, XLP, Hodgkin L, post-transplant L KSHV (HHV8)Kaposis S, Primary effusion L, Castelmans

30 Virus induced oncogenesis ONCOPROTEINS Variants of cellular genes (HHV8, transducing retroviruses) Viral regulatory proteins not obviously related to cellular genes short amino acid sequence homology precise origins not clear

31 KSHV (HHV8) V-Gpcr EBV LMP-1 HBV pX (Ras) LHB (PKC) HTLV-1 Tax EBV EBNA-2 LMP-1 HBV pX Permanent activation of cell signal transduction pathways NF- B

32 M G1 S G2 Rb P Proteins of retinoblastoma (Rb) control cell cycle retinoblastoma P Cyclins D+Cdk2,4,6 Disruption of regulation of cell cycle progression G1/S restriction point G2/M restriction point p21 CIP

33 Functional inactivation of retinoblastoma protein Increased synthesis of cellular and some viral replication proteins HPV protein E7 KSHV v-CYC (cdk6) SV40 LT Inhibition of synthesis of cellular and some viral replication proteins Cyclins D Cdk2,4,6

34 M G1 S G2 Rb P p53 apoptose Cell stress oncogene expression in absence of growth factors Irradiation Proteins of retinoblastoma (Rb) and p53 control cell cycle and apoptosis retinoblastoma P Cyclins D+Cdk2,4,6 Disruption of regulation of cell cycle progression and cell death (apoptosis) G1/S restriction point G2/M restriction point p21 CIP

35 Inactivation of protein p53 by virale proteins Protein level - ubiquitinylation - proteasome degradation HPVE6-E6Ap - sequestration in cytoplasma HCV NS5A HBV pX Transcription level - HHV8 LANA2

36 Inactivation of protein p53 by virale proteins Protein level - ubiquitinylation - proteasome degradation HPVE6-E6Ap - sequestration in cytoplasma HCV NS5A HBV pX Transcription level - HHV8 LANA2

37 Telomere erosion: restriction of proliferative capacity Telomerase reverse transcriptase (TERT) Cell immortalization Anti-replicative senescence

38 Oncoproteins of human cancer-related viruses virusSignal transduction pathway Cell cycleApoptosisSenescence (telomerase) HCV corecore (TNFR) NS5A (p53 sequestr) HTLV-1 taxtax (G1/S) (inhibit G2/M) HBV pX HPV E6E7 (G1/S)E6 (p53 ubiquitin)E6 EBV LMP-1 EBNA-2 EBNA-1BHRF1 BALF1 LMP1 KSHV (HHV8) V-GpcrLANA-1 v-Cyc (G1/S) K-bZIP/RAP (inhibits G2/M) LANA-1 LANA-2 (p53 trancr) V-Bcl2 (Bax) V-IAP (Casp3) V-IRF-1(CBP/p300) LANA-1 Pleiotropic effect

39 Viral hepatitis and hepatocellular carcinoma (HCC)

40 Pathogenesis of virus induced HCC Leading hypothesis Indirect effect Chronic HBV/HCV infection virus induced immunological killing Hepatocyte proliferation mutations cancerogenesis Inflammation and phagocytosis superoxides and free radicals Direct effect Chronic viral infection virus products cancerogenesis

41 Oncoproteins are not clearly defined Lack of adequate models HBV and HCV replicates in cancer cells Pathogenesis of virus induced HCC chronicityQuasi- species Integrationcirrhosisoncogene HBV10% %pX HCV60-80%+-5-10%Core NS5A Are viral gene products necessary for establishment of cancer? Does the cancer become independent of virus?

42 Pathogenesis of virus induced HCC is a complex process

43 Vaccination against HAV, HBV No vaccine against HCV Vaccination against HCC Which immunogen select? Are viral proteins potential candidates?


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