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Ivan Hirsch Institut de Cancérologie de Marseille, UMR 599 INSERM

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Presentation on theme: "Ivan Hirsch Institut de Cancérologie de Marseille, UMR 599 INSERM"— Presentation transcript:

1 Ivan Hirsch Institut de Cancérologie de Marseille, UMR 599 INSERM Institut Paoli-Calmettes Université de la Méditerranée 27, boulevard Lei Roure 13009 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)
+ADN rétrovirus +ARN -ADN ±ADN HBV +ARN -ARN +ARNm ±ARN HAV HCV HEV -ARN

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

7 Virus à l’ARN + : Organisation du génome
Virus de la hépatite A Virus à l’ARN + : Organisation du génome

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

9

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

11 Mécanismes de le restriction virale Virus à l’ARN : interféron

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

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

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

15 Cycle réplicatif du virus de l’hépatite B (HBV)

16

17

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

19 Pathogenèse

20 Pathogenèse de l’infection par le virus de la hépatite A

21 Pathogenèse de l’infection par le virus de la hépatite B et C

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

23 Virus et cancer

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

25 Oncogene (2003), TM Block, R. Jordan
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
gag pol env LTR LTR oncogene Permanent activation of cell signal transduction 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 Seminal role in the cancerogenesis research

29 Oncogenic viruses and cancer
Viral family associated human cancer RNA viruses Flaviviridae HCV hepatocellular carcinoma  cytoplasma Retroviridae HTLV T cell leukemia HIV carcinomas, lymphomas DNA viruses Hepadnaviridae HBV hepatocellular carcinoma  Papillomaviridae HPV16,18 cervical carcinoma  Herpesviridae EBV BL, NPC, XLP, Hodgkin L, post-transplant L KSHV (HHV8) Kaposi’s S, Primary effusion L, Castelman’s

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

32 Disruption of regulation of cell cycle progression
retinoblastoma Rb G2/M restriction point M G2 Cyclins D+Cdk2,4,6 G1 p21CIP P Rb P S G1/S restriction point Proteins of retinoblastoma (Rb) control cell cycle

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

34 Disruption of regulation of cell cycle progression
and cell death (apoptosis) oncogene expression in absence of growth factors Irradiation Cell stress retinoblastoma Rb p53 apoptose G2/M restriction point M G2 G1 p21CIP Cyclins D+Cdk2,4,6 P Rb P S G1/S restriction point Proteins of retinoblastoma (Rb) and p53 control cell cycle and apoptosis

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
Signal transduction pathway Cell cycle Apoptosis Senescence (telomerase) HCV core core (TNFR) NS5A (p53 sequestr) HTLV-1 tax tax (G1/S) (inhibit G2/M) HBV pX HPV E6 E7 (G1/S) E6 (p53 ubiquitin) EBV LMP-1 EBNA-2 EBNA-1 BHRF1 BALF1 LMP1 KSHV (HHV8) V-Gpcr LANA-1 v-Cyc (G1/S) K-bZIP/RAP (inhibits G2/M) LANA-2 (p53 trancr) V-Bcl2 (Bax) V-IAP (Casp3) V-IRF-1(CBP/p300) Pleiotropic effect

39 hepatocellular carcinoma (HCC)
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 Pathogenesis of virus induced HCC
Oncoproteins are not clearly defined Lack of adequate models HBV and HCV replicates in cancer cells chronicity Quasi-species Integration cirrhosis oncogene HBV 10% - + 0.2-1% pX HCV 60-80% 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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