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Human immune response to Hepatitis C virus

Human immune response to Hepatitis C virus. Geert Leroux-Roels Center for Vaccinology Ghent University and Hospital. Overview of the presentation. The principal actors Hepatitis C virus or HCV The human immune system Innate immune system Adaptive immune response

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Human immune response to Hepatitis C virus

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  1. Human immune response to Hepatitis C virus Geert Leroux-Roels Center for Vaccinology Ghent University and Hospital

  2. Overview of the presentation • The principal actors • Hepatitis C virus or HCV • The human immune system • Innate immune system • Adaptive immune response • Mechanisms of persistence • Consequences for vaccine development

  3. The HCV genome and expressed polyprotein Lauer et al. NEJM 345:41-52, 2001

  4. Envelope proteins E1 (gp31) E2 (gp70) Nucleoprotein - Core (p21) RNA genome Hepatitis C virus

  5. Y Y Y Y Y CD8+ CTL CD4+ Th cell NK APC NKT cells The human immune response B cell Hepatocyte

  6. Study of the immune response • Patient studies • Animal models

  7. 20% Spontaneous clearance Acute infection 80% Treatment Chronic infection No response Sustained response Chronic hepatitis Patient Studies

  8. Patient studies Liver infiltrating lymphocytes - fresh - cultured Liver infiltrating lymphocytes PBMC - fresh - cultured

  9. Study of the immune response • Patient studies • Animal models • chimpanzee(ethics, = human) • mouse models • HLA-A2 transgenic mouse • HCV transgenic mice • huPBL-SCID mouse, Trimera mouse, huHepatocyte-uPA-SCID mouse, ..

  10. a-NS3 Y B cell Y a-E2 a-E1 Y Lysis Hepatocyte CD8+ CTL CD4+ Th cell TNF-a IFN-g IFN-g APC The adaptive immune response to HCV

  11. Kinetics of anti-HCV response in patients with transfusion- associated hepatitis C and resolution of infection Chen et al. Gastroenterology 1999;116:135-143

  12. Kinetics of anti-HCV response in patients with transfusion- associated hepatitis C who develop chronic HCV Chen et al. Gastroenterology 1999;116:135-143

  13. Target of neutralizing antibodies • Envelope proteins E1 and E2 • Protective role demonstrated by in vitro neutralization of chimpanzee- infectious HCV with antibody • directed against HVR1 and other regions of E2

  14. Neutralisation of binding -NOB assay HVR1 E1 E2 CD81 MOLT 4 CD81

  15. Are antibodies needed to clear HCV infection ? • Human HCV infection can resolve in agammaglobulinemic children • Bjoro et al. NEJM 1194; 331:1607-1611 • Adams et al. Ped Inf Dis J 1997;16:533-534 • Christie et al. Clin Exp Immunol 1997;110:4-8 • HCV clearance in chimp occurred in the absence of any antibody response to envelope proteins • Bassett et al. J Virol 1999;73:1118-1126

  16. Proliferative CD4+ T-cell response in the acute phase of disease to recombinant HCV proteins in 38 patients with acute HCV infection Gerlach et al. Gastroenterology 1999;117:933-941

  17. Immune response during acute and chronic HCV infections

  18. Correlate of protection and disease progression ?

  19. antibodies to most structural and non-structural viral proteins are made Y Y Y Y Y - vigorous, multi- specific response - CTL exert some control on viral load - early, vigorous, multi- specific response - strong NS3-response in resolving acute HCV - TH1 in recovery - TH2 in chronic NK NKT cells Role largely unknown Immune response to HCV infection : B cell CD8+ CTL Hepatocyte CD4+ Th cell

  20. Potential Mechanisms of Viral Persistence • Inadequate HCV-specific IR • inadequate innate immune response • insufficient induction of adaptive IR • inability to maintain the adaptive IR • Viral evasion mechanisms

  21. Potential Mechanisms of Viral Persistence • Inadequate HCV-specific IR • inadequate innate immune response • NK Cell function • Dendritic cell function • insufficient induction of adaptive IR • inability to maintain the adaptive IR

  22. Effect of HCV on NK cell function HCV NK cell (in vitro) Binding of HCV E2 protein to CD81 on NK cell causes inhibition of - cytolytic activity - IFN-g production E1 CD81 E2 CD81 Crotta et al. JEM 2002;195:35-41 Tseng et al. JEM 2002;195:43-49

  23. Effect of HCV on NK cell function Natural cytotoxicity and antibody-dependent cytotoxicity (ADCC) is not impaired in patients suffering from chronic hepatitis C Düesberg U, Schneiders A, Flieger D, Inchauspé G, Sauerbruch T, Spengler U. J Hepatol 2001;35:650-657

  24. Potential Mechanisms of Viral Persistence • Inadequate HCV-specific IR • insufficient induction of adaptive IR • low level of viral antigen expression • virus infection of antigen-presenting cells and dendritic cell function • inappropriate cytokine profile of TH • lack or low frequency of neutralizing antibodies

  25. Liver and extra-hepatic infection sites Liver 2x1011 hepatocytes Spleen & Lymphoid tissue B lymphocyte Monocyte Dendritic cell BDEC ? Pancreas Kidney

  26. Dendritic cell maturation Dendritic cell precursor - Monocyte IL-4 + GM-CSF LPS/TNFa Janeway-Immunobiology

  27. Reduced capacity of mature DC from HCV patients to induce allogeneic T cell proliferation. Bain et al. Gastroenterology 120:51-524, 2001

  28. IL-2 production and percentages of CD4+/CD25+ cells in response to HCV core or TT antigens in HCV patients Sarobe et al. J.Virol 76:5062-5070, 2002

  29. Potential Mechanisms of Viral Persistence • Inadequate HCV-specific IR • inadequate innate immune response • insufficient induction of adaptive IR • inability to maintain the adaptive IR • Viral evasion mechanisms

  30. Potential Mechanisms of Viral Persistence • Viral evasion mechanisms • replication in immune privileged sites • viral interference with antigen processing • viral suppression of host immune response • viral sequence variation • viral insusceptibility to cytokine mediated inhibition of replication and gene expression

  31. Potential Mechanisms of Viral Persistence • Viral evasion mechanisms • replication in immune privileged sites • viral interference with antigen processing • viral suppression of host immune response • viral sequence variation • viral insusceptibility to cytokine mediated inhibition of replication and gene expression

  32. HCV core controversy The Journal of Immunology, 2001, 167: 5264-5272.Hepatitis C Virus Core Protein Inhibits Human T Lymphocyte Responses by a Complement-Dependent Regulatory Pathway1,2 Zhi Qiang Yao, Duong Tony Nguyen, Apostolos I. Hiotellis and Young S. Hahn3 Journal of Virology, February 2002, p. 990-997, Vol. 76, No. 3 Hepatitis C Virus Genotype 1b Core Protein Does Not Exert Immunomodulatory Effects on Virus-Induced Cellular Immunity Zhang-Xu Liu,1 Hiroshi Nishida,1 Jian-Wen He,1,2 Michael M. C. Lai,1,2 Ni Feng,1 and Gunther Dennert1*

  33. Potential Mechanisms of Viral Persistence • Viral evasion mechanisms • replication in immune privileged sites • viral interference with antigen processing • viral suppression of host immune response • viral sequence variation • escape from humoral immune response • escape from cellular immune response • viral insusceptibility to cytokine ...

  34. NS2 NS3 NS4B NS5A NS5B 3’ 5’UT C E1 E2 p7 Variability of HCV • 6 major genotypes • more than 50 subtypes • Quasispecies Hypervariable region - HVR1 384410 cross-reactivity (%) R9 QTTVVGGSQSHTVRGLTSLFSPGASQN 60 F78 QTHTTGGGAGHQAHSLTGLFSPGAKQN 70 M122 QTTTTGGSAHAVSSLTGLFSPGSKQN 44 G31 TTHTVGGSVARQVHSLTGLFSPGPQQK 77 H1 QTHTTGGVVGHATSGLTSLFSPGPSQK 42 D6 QTTTTGGQVSHATHGLTGLFSLGPQQK 66

  35. Potential Mechanisms of Viral Persistence • Viral evasion mechanisms • replication in immune privileged sites • viral interference with antigen processing • viral suppression of host immune response • viral sequence variation • viral insusceptibility to cytokine mediated inhibition of replication and gene expression

  36. IFN Protein Kinase PKR inactive HCV E1 HCV NS5A dsRNA ssRNA Protein Kinase PKR active Phosphorylated Initiation Factor eIF-2a P Initiation Factor eIF-2a Pi Phosphatase (soluble) mRNA translation inhibition Antagonism of IFN by HCV proteins

  37. Development of HCV vaccines badly needs • Better understanding of mechanisms of immune protection and clearance • Development of tissue culture system and small animal model of HCV infection

  38. Dendritic cell maturation Jacques Banchereau et al. Immunobiology of Dendritic Cells Annu. Rev. Immunol. 2000. 18:767-811.

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