Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Présentation PowerPoint
Document related concepts
no text concepts found
Transcript
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)4-91 758415 Fax : +33-(0)4-91 260364 Email : [email protected] Web site: http://u119.marseille.inserm.fr/ Hépatite C et le système immunitaire Réplication virale Infection chronique Immunité innée Interférons du type I Cellules dendritiques plasmacytoïdes Cancer hépatocellulaire Familles de virus à ARN humains et animaux polari té ARN géno mique taille (kb) ARNm + sb " Un 7.28.4 Taille de géno me " " Un " " Un Un " Diploide 4-10 " sb " " Un 16-20 Une protéine " " " 7-8 segments +/-sb " Un 10-12 Un Un Enzyme s dans le virion - Protéine - picornaviridae Entero-: poliomyélite, CardioHepato-: hépatite A, Rhino- - " + flaviviri dae - - + alphaviridae hépatite C, fièvres hémorragiques: fièvre jaune, virus de la dengue, encé phalite de St.Louis rubéole , virus de Sindbis (SV), virus de la foret de Semliki (SFV) - - + - coronaviridae calicivirid ae ARNt + retroviridae Trans criptase + + - + rhabdoviridae - + + filoviridae paramyxoviridae Ebola, Marbu rg " + + orthomyxoviridae grippe " " + + ARNm cellulaire " " + + bunya viridae arenaviridae Fièvre hémorragique, Hantavirus " + - - reoviridae rotavirus, ma ladie fébrile " i nfantiles + - - birnaviridae "bursal disease of chickens " Subgéno mique " " 14 3 segments 13-21 2 segments 10-14 “circ” db 8-12 22-27 segme nts " 2 segments 7 Soulignements : hЋpatites; maladies RT,PR,IN amorce enveloppe Nom de famille "comm on col d pneumonia" hépatite E, gastroentérite retro- (RSV), lenti- (VIH, SIV, HTLV), spumavirus de la stomatite vésiculaire (VSV), rage, rougeole, oreillons, parainfluenza Lassa, Machupo, virus de la Chorioméningite lymp hocytaire (LCMV) Familles de àvirus humains et animaux Familles de virus ADN humains et animaux géno me DNA sb/d Circulaire b sb Circulaire (+/) db Circulaire linéaire Linéaire (L/S reg.) linéaire taille (kb) Enzyme s structur ales dans le virion réplication 3.2 RT, protéine kinase (PK) noy au + noy au 5-8 36-38 120200 130350 5 DNA pol, PR, 3 PK. DNA, RNA pol Soulignements : hépatites; maladies infantiles enveloppe assemblage Nom de famille hepadnaviridae hépatite B (HBV) - intracyt. vesic noy au parvoviridae 5ème maladi e (érythéma) arthrite rhumatoïde noy au - noy au papovaviridae noy au noy au + cytoplasme + noy au adenoviridae Membrane herpesviridae nucléaire cytoplasme poxviridae papilloma (>50 types) polyoma JC, SV40 Adéno (48 types) HSV-1&2, CMV, VZV, EBV, HHV-6 (roséole), HHV-7, KSHV (HHV-8) vacci ne, variole Classification de virus (David Baltimore) +ADN rétrovirus +ARN -ADN +ARN -ARN HAV HCV HEV ±ADN HBV +ARNm -ARN ±ARN HCV target cells Dendritic cell Hepatocytes Lymphocytes B T Kupffer cell Failure to develop general and efficient permissive system for HCV replication in vitro Virus de la hépatite C Virus à l’ARN + : Organisation du génome Poliomyélite Hépatite A, C Fièvre jaune Resistance to IFN-a C polyprotéine structurales Protéines non-structurales ARNm Core Envelope glycoprotein Serine protease domaines protéolytiques Impairment of production of IFN-a Virus de la hépatite A Virus à l’ARN + : Organisation du génome HAV, HCV - Virus à ARN + : cycle viral Hépatocyte Receptor inhibitors Vaccines Monoclonal antibodies P7 Inhibitors? NS3-helicase and NS5B-Polymerase inhibitors Membrane-association Intervention? NS2-NS3 and NS3-4A Protease inhibitors HCV E1/E2 CD81 LDLR Single-stranded RNA and core (nucleocapsid) replicase Ribavirin IFN-a HCV therapy IFN-a, ribavirin clinical resolution in ≥50% cases (genotype dependent) Protease inhibitors (phase 3) Polymerase inhibitors (phase 3) Mécanismes de le restriction virale Virus à l’ARN : interféron Mechanism of viral detection TLR (Toll-like receptor) dsRNA-TLR3 endosome TLR7-ssRNA TLR8-ssRNA TLR9-dsDNA CARD-helicases sensors helicase RIG-1 MDA-5 CARD TRIF MyD88 adaptators MAVS, IPS-1 VISA, CARDIF 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 RIG-1-dependent mechanism of IFN-b induction in hepatocytes pDC Anti-HCV therapy IFN-a CD81 LDLR replication RIG-1 MDA-5 helicases NS3/4A CARD CARDIF TBK-1 IKK-e IRF3 NF-kB AP-1 nucleus IFN-b HCV infection: delicate equilibrium between virus replication and IFN-a/b interference Virus de la hépatite B Hepadna virus : Organisation du génome middle Large small (+) strand (-) strand Polymerase Core X Cycle réplicatif du virus de l’hépatite B (HBV) Mécanismes de la restriction virale Virus avec transcriptase inverse : APOBEC3G Pathogenèse Pathogenèse de l’infection par le virus de la hépatite A Pathogenèse de l’infection par le virus de la hépatite B et C QuickTime™ et un décompresseur TIFF (LZW) sont requis pour visionner cette image. acute hepatitis Pathogenèse de l’infection par le virus de la hépatite B et C Time line of cumulative morbidity during chronic infection HCC cirrhosis hepatitis inactive hepatitis Chronicité 0% HAV 10% HBV 70% HCV Virus et cancer HCV/HBV pathogenesis Death due to the five most common cancer diagnoses in 2001 Oncogene (2003), TM Block, R. Jordan Viral etiology of HCC Oncogene (2003), TM Block, R. Jordan 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) 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 Oncogene transducing retroviruses paradigm LTR gag pol oncogene env LTR 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 Oncogenic viruses and cancer Viral family RNA viruses Flaviviridae Retroviridae associated human cancer HCV HTLV HIV hepatocellular carcinoma cytoplasma T cell leukemia carcinomas, lymphomas Hepadnaviridae Papillomaviridae HBV HPV16,18 hepatocellular carcinoma cervical carcinoma Herpesviridae EBV KSHV (HHV8) BL, NPC, XLP, Hodgkin L, post-transplant L Kaposi’s S, Primary effusion L, Castelman’s DNA viruses 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 Permanent activation of cell signal transduction pathways HBV pX KSHV (HHV8) V-Gpcr EBV LMP-1 HBV NF-kB HTLV-1 EBV pX (Ras) LHB (PKC) Tax EBNA-2 LMP-1 Disruption of regulation of cell cycle progression retinoblastoma Rb G2/M restriction point G2 p21CIP M G1 Cyclins D+Cdk2,4,6 Rb S P P G1/S restriction point Proteins of retinoblastoma (Rb) control cell cycle 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 Dp Dp Inhibition of synthesis of cellular and some viral replication proteins Disruption of regulation of cell cycle progression and cell death (apoptosis) Cell stress retinoblastoma Rb G2/M restriction point G2 p21CIP • oncogene expression in absence of growth factors • Irradiation apoptose p53 M G1 Cyclins D+Cdk2,4,6 Rb S P P G1/S restriction point Proteins of retinoblastoma (Rb) and p53 control cell cycle and apoptosis 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 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 Telomere erosion: restriction of proliferative capacity Cell immortalization Anti-replicative senescence Telomerase reverse transcriptase (TERT) Oncoproteins of human cancer-related viruses virus Signal transduction pathway HCV core HTLV-1 tax HBV pX HPV E6 EBV KSHV (HHV8) Cell cycle Apoptosis Senescence (telomerase) core (TNFR) NS5A (p53 sequestr) tax (G1/S) (inhibit G2/M) pX pX E7 (G1/S) E6 (p53 ubiquitin) E6 LMP-1 EBNA-2 EBNA-1 BHRF1 BALF1 LMP1 V-Gpcr LANA-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 Viral hepatitis and hepatocellular carcinoma (HCC) 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 Pathogenesis of virus induced HCC • Oncoproteins are not clearly defined Lack of adequate models HBV and HCV replicates in cancer cells chronicity Quasispecies 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? Pathogenesis of virus induced HCC is a complex process Vaccination against HAV, HBV No vaccine against HCV Vaccination against HCC Which immunogen select? Are viral proteins potential candidates?
