Introduction to Human Immune Respose to Hepatitis C virus by AmnaKhan

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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

Hepatocyte

CD4+ Th cell

NK

APC
NKT
cells

Study of the immune response

• Patient studies
• Animal models

Patient Studies
Acute infection
80% 20%

Spontaneous clearance

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+ CTL
TNF-a IFN-g

Hepatocyte

CD4+ Th cell
IFN-g

APC

Kinetics of anti-HCV response in patients with transfusionassociated hepatitis C and resolution of infection

Chen et al. Gastroenterology 1999;116:135-143

Kinetics of anti-HCV response in patients with transfusionassociated 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 chimpanzeeinfectious HCV with antibody • directed against HVR1 and other regions of E2

Neutralisation of binding NOB assay
E1
HVR1

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
Acute/SelfType of limiting response
PBMC

Chronic HCV
PBMC Liver

B cell (Ab) CD4 CD8

Low titered, against few proteins Early, multispecific Early, multispecific

High titered, against most proteins Low, pauci- Present, specific pauci-specific Low, paucispecific Present, 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, multispecific response - CTL exert some control on viral load

CD8+ CTL

Hepatocyte

CD4+ Th cell

NK
Role largely unknown

NKT
cells

- early, vigorous, multispecific response - strong NS3-response in resolving acute HCV - TH1 in recovery - TH2 in chronic

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
E1 E2
CD81

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

CD81

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 Monocyte Dendritic cell

BDEC

?
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’

Hypervariable region - HVR1
384 R9 F78 M122 G31 H1 D6

• 6 major genotypes • more than 50 subtypes • Quasispecies
410 cross-reactivity (%) 60 70 44 77 42 66

QTTVVGGSQSHTVRGLTSLFSPGASQN QTHTTGGGAGHQAHSLTGLFSPGAKQN QTTTTGGSAHAVSSLTGLFSPGSKQN TTHTVGGSVARQVHSLTGLFSPGPQQK QTHTTGGVVGHATSGLTSLFSPGPSQK QTTTTGGQVSHATHGLTGLFSLGPQQK

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 dsRNA ssRNA

inactive

HCV E1 HCV NS5A
Phosphorylated Initiation Factor

Protein Kinase PKR

active

Initiation Factor

eIF-2a

Pi

eIF-2a P

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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