human immune response to hepatitis c virus geert leroux-roels center for vaccinology ghent...
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Human immune response to Hepatitis C
virus
Geert Leroux-RoelsCenter for Vaccinology
Ghent University and Hospital
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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
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The HCV genome and expressed polyprotein
Lauer et al. NEJM 345:41-52, 2001
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Hepatitis C virus
Envelope proteins E1 (gp31) E2 (gp70)
Nucleoprotein- Core (p21)
RNA genome
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B cell
Hepatocyte
CD8+
CTL CD4+Th cell
YY
Y
YY
APCNK
NKTcells
The human immune response
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Study of the immune response
•Patient studies
•Animal models
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Acute infectionSpontaneous
clearance
Chronic infection
20%
80%
Treatment
Chronic hepatitis
No response
Sustained response
Patient Studies
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Patient studies
Liver infiltrating lymphocytes
PBMC
- fresh- cultured
Liver infiltrating lymphocytes
- fresh - cultured
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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, ..
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The adaptive immune response to HCV
CD4+Th cell
CD8+
CTL
TNF-IFN-
Lysis
IFN-
Hepatocyte
APC
YY
B cellY-E1-E2
-NS3
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Kinetics of anti-HCV response in patients with transfusion-associated hepatitis C and resolution of infection
Chen et al. Gastroenterology 1999;116:135-143
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Kinetics of anti-HCV response in patients with transfusion-associated hepatitis C who develop chronic HCV
Chen et al. Gastroenterology 1999;116:135-143
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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
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Neutralisation of binding -NOB assay
CD81 MOLT 4 CD81
HVR1
E2
E1
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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
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Gerlach et al. Gastroenterology 1999;117:933-941
Proliferative CD4+ T-cell response in the acute phase of disease to recombinant HCV proteins in 38 patients with acute HCV infection
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Immune response during acute and chronic HCV infections
Type ofresponse
Acute/ Self-limiting
Chronic HCV
PBMC PBMC Liver
B cell(Ab)
Low titered,against fewproteins
High titered,against mostproteins
CD4 Early, multi-specific
Low, pauci-specific
Present,pauci-specific
CD8 Early, multi-specific
Low, pauci-specific
Present,pauci-specific
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Correlate of protection and disease
progression ?
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B cell
CD8+
CTL HepatocyteCD4+
Th cell
YY
Y
YY
NK
NKTcells
Immune response to HCV infection :
Role largely unknown
- early, vigorous, multi- specific response- strong NS3-response in resolving acute HCV- TH1 in recovery- TH2 in chronic
- vigorous, multi- specific response- CTL exert some control on viral load
antibodies to most structural and non-structural viral proteins are made
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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
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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
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Effect of HCV on NK cell function
CD81
CD81
NK cell (in vitro)HCV
Binding of HCV E2 proteinto CD81 on NK cell causesinhibition of - cytolytic activity- IFN- production
Crotta et al. JEM 2002;195:35-41Tseng et al. JEM 2002;195:43-49
E2
E1
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Effect of HCV on NK cell function
Natural cytotoxicity and antibody-dependentcytotoxicity (ADCC) is not impaired in patientssuffering from chronic hepatitis C
Düesberg U, Schneiders A, Flieger D, Inchauspé G, Sauerbruch T, Spengler U.
J Hepatol 2001;35:650-657
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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
cellsand dendritic cell function
• inappropriate cytokine profile of TH
• lack or low frequency of neutralizing antibodies
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Liver 2x1011 hepatocytes
Kidney Pancreas
Spleen &Lymphoid tissue
B lymphocyteMonocyte
Dendritic cell
Liver and extra-hepatic infection sites
BDEC
?
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Janeway-Immunobiology
Dendritic cell precursor - Monocyte
IL-4 + GM-CSF
LPS/TNF
Dendritic cell maturation
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Reduced capacity of mature DC from HCV patients to induce allogeneic T cell proliferation.
Bain et al. Gastroenterology 120:51-524, 2001
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IL-2 production andpercentages of CD4+/CD25+ cellsin response to HCVcore or TT antigensin HCV patients
Sarobe et al.J.Virol 76:5062-5070, 2002
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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
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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
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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
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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
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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 ...
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Variability of HCV
• 6 major genotypes• more than 50
subtypes• Quasispecies
5’UT C E1 E2 p7 NS2 NS4BNS3 NS5A NS5B 3’
Hypervariable region - HVR1
384 410 cross-reactivity (%)
R9 QTTVVGGSQSHTVRGLTSLFSPGASQN 60 F78 QTHTTGGGAGHQAHSLTGLFSPGAKQN 70M122 QTTTTGGSAHAVSSLTGLFSPGSKQN 44G31 TTHTVGGSVARQVHSLTGLFSPGPQQK 77H1 QTHTTGGVVGHATSGLTSLFSPGPSQK 42D6 QTTTTGGQVSHATHGLTGLFSLGPQQK 66
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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
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Antagonism of IFN by HCV proteins
IFN
Protein Kinase PKRinactive
Initiation FactoreIF-2
PhosphorylatedInitiation FactoreIF-2P
Phosphatase(soluble)
Pi
mRNA translation inhibition
Protein Kinase PKRactive
dsRNAssRNA
HCV E1 HCV NS5A
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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
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Dendritic cell maturation
Jacques Banchereau et al.Immunobiology of Dendritic Cells Annu. Rev. Immunol. 2000. 18:767-811.