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					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

• Mechanisms of persistence
• Consequences for vaccine development
The HCV genome and expressed polyprotein




                      Lauer et al. NEJM 345:41-52, 2001
Hepatitis C virus

            Envelope proteins
             E1 (gp31)
             E2 (gp70)




            Nucleoprotein
             - Core (p21)

            RNA genome
The human immune response


                        B cell




   CD8+
   CTL                           CD4+
           Hepatocyte            Th cell




      NK
                        APC
           NKT
           cells
Study of the immune response

• Patient studies

• Animal models
Patient Studies
                     20%      Spontaneous
Acute infection
                                clearance

  80%



Chronic infection                 Treatment



                    No response
                                      Sustained
                                       response
Chronic hepatitis
             Patient studies

Liver infiltrating lymphocytes

- fresh
- cultured

                                 PBMC

                                 - fresh
                                 - cultured
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, ..
The adaptive immune response to HCV
       a-NS3

     a-E2   a-E1     B cell



                   Lysis

                            CD8+
    Hepatocyte              CTL


                    TNF-a
                                    CD4+
                    IFN-g           Th cell

                                    IFN-g

                              APC
Kinetics of anti-HCV response in patients with transfusion-
associated hepatitis C and resolution of infection




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




                                        Chen et al.
                                        Gastroenterology 1999;116:135-143
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
Neutralisation of binding -
        NOB assay

                 HVR1
     E1


E2



          CD81   MOLT 4   CD81
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
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
 Immune response during
 acute and chronic HCV infections

Type of  Acute/Self-              Chronic HCV
response   limiting
               PBMC           PBMC            Liver
  B cell   Low titered,    High titered,
  (Ab)     against few     against most
           proteins        proteins
  CD4      Early, multi-   Low, pauci- Present,
           specific        specific      pauci-specific
  CD8      Early, multi-   Low, pauci-   Present,
           specific        specific      pauci-specific
 Correlate of protection
and disease progression ?
             Immune response to HCV infection :
antibodies to most structural and
non-structural viral proteins are made

                                                 B cell

- vigorous, multi-
  specific response
- CTL exert some
                      CD8+
  control on viral                                         CD4+
                      CTL          Hepatocyte
  load                                                    Th cell



                                                   - early, vigorous, multi-
                                                     specific response
                             NK                    - strong NS3-response
                                                     in resolving acute HCV
                                         NKT       - TH1 in recovery
                         Role largely    cells     - TH2 in chronic
                          unknown
       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
       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
     Effect of HCV on NK cell function

      HCV                 NK cell (in vitro)
                          Binding of HCV E2 protein
 E1                CD81   to CD81 on NK cell causes
E2                        inhibition of
                          - cytolytic activity
                          - IFN-g production
            CD81

                           Crotta et al. JEM 2002;195:35-41
                           Tseng et al. JEM 2002;195:43-49
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
      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
Liver and extra-hepatic infection sites
                Liver
                2x1011 hepatocytes      Spleen &
                                     Lymphoid tissue


                                      B lymphocyte
BDEC                                    Monocyte
                                      Dendritic cell




                        ?
       Kidney                        Pancreas
Dendritic cell maturation
Dendritic cell precursor - Monocyte



                  IL-4 + GM-CSF




                               LPS/TNFa




                                          Janeway-Immunobiology
Reduced capacity of mature DC from HCV
patients to induce allogeneic T cell proliferation.




                     Bain et al. Gastroenterology 120:51-524, 2001
 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
      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
       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
       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
  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*
       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 ...
                 Variability of HCV

5’UT     C     E1    E2   p7 NS2      NS3         NS4B       NS5A NS5B   3’



                                • 6 major genotypes
                                • more than 50 subtypes
                                • Quasispecies
Hypervariable region - HVR1
  384                           410   cross-reactivity (%)
R9     QTTVVGGSQSHTVRGLTSLFSPGASQN           60
F78    QTHTTGGGAGHQAHSLTGLFSPGAKQN           70
M122   QTTTTGGSAHAVSSLTGLFSPGSKQN            44
G31    TTHTVGGSVARQVHSLTGLFSPGPQQK           77
H1     QTHTTGGVVGHATSGLTSLFSPGPSQK           42
D6     QTTTTGGQVSHATHGLTGLFSLGPQQK           66
       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
Antagonism of IFN by HCV proteins

                           IFN


               Protein Kinase PKR
                          inactive
     dsRNA                                       HCV E1
     ssRNA                                       HCV NS5A
               Protein Kinase PKR
                          active
 Initiation Factor                    Phosphorylated
      eIF-2a                          Initiation Factor
                                      eIF-2a P
                     Pi
        Phosphatase
           (soluble)
                                   mRNA translation inhibition
 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
  Dendritic cell
  maturation




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

				
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