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Hepatitis C Around the World
Americas13.1 million
(1.7%)
Eastern Mediterranean
21.3 million(4.6%)
Africa31.9 million
(5.3%)
Southeast Asia32.3 million
(2.15%)
Europe8.9 million
(1.03%)
Western Pacific62.2 million
(3.9%)
World: 169.7 million (3.1%) prevalent cases
Reported rates of acute HCV infection by age group in Canada, 2004-2008
Male Female
• An estimated 242,500 people in Canada were infected with HCV as of December 2007 (0.7% of total population).
• In 2007, approximately 7,900 people in Canada were estimated to be newly infected with HCV.
• 21 percent of those infected with HCV are unaware of their infection.
Reported rate of acute HCV infection in Canada, 2004-2008
Epidemiology of HCV Infection in Canada(Public Health Agency of Canada)
HCV Infection: Transmission Routes
Distribution of mutually exclusive risk factors for newly-Acquired HCV
infection among cases with known risk factor
Canada 2004-2008
Blood to blood contact:
1. Shared needle in IV drug abusers.2. Vertical Transmission (Mother to Child).3. Percutaneous procedures. 4. Needle accident in health care providers.5. Contaminated blood products (rare)6. Others
Natural History of Hepatitis C
HCV Infection
Acute Hepatitis
Chronic Infection
Resolve Fulminant Hepatitis
HCCCirrhosis
Chronic Active Hepatitis
15-25% Rare75-85%
10-20% in 20 years
1-4%/year
Decompensated Cirrhosis, primary etiology of liver transplantation.
Bosch and others 1999, Sharma and Lok 2006
HCC, the third leading cause of cancer death worldwide.
Bosch and others 1999, Sharma and Lok 2006
Diagnostic tools for HCVScreening test: Enzyme Immunoassay (EIA), 3rd and 4th generation, Sensitive but low PPV
Confirmation tests:• Immunoblot analysis 3rd generation (RIBA), rarely used • Nucleic Acid Tests (NATs): Specific and Sensitive.
Scott JD, Gretch DR, JAMA 2008
Burlone, ME, et.al. J Gen Virol, 2009
HCV Life Cycle: Cell Entry
Lukavsky, PJ. Virus Research, 2009
HCV Life Cycle: RNA Translation
HCV Life Cycle: Assembly
HCV Life Cycle: Secretion as LVP
Immunopathogenesis of HCV Infection: Innate response of hepatocytes
Important ISGs that are activated by IFNβ:
Protein Kinase R (PKR): Phosphorylation of eIF2 and inhibition of HCV RNA translation.
Pflugheber, J., et al. PNAS, 2002.
ISG56: Phosphorylation of eIF3: and inhibition of HCV RNA translationHui, D.J., et al. JBC, 2003.
Adenosine Deaminase (ADAR1): converts adenosine residues into inosine residues in dsRNA strands, thereby mutating and destabilizing secondary viral RNA structures.
Taylor, D.R., et.al. J Virol, 2005.
Viperin: Crystallizes ER membrane, interferes with replication complex.Hinson and Cresswell 2009.
Rehermann, B. J Clin Invest, 2009
Innate Immune Cells:
NKT cells: 1. regulates the balance between Th1 and Th2 response and cytokine
production.2. In HCV infected liver they may secret cytokines negative effect on T cell
activation (IL-10, TGF-β).
NK Cells:3. Early in infection can kill the cells with high stimulatory/low inhibitory
signals.4. KIR2DL3 receptor and HLA-C1 are associated with very low inhibitory signal,
more likely to clear HCV. Khakoo, SI, et.al, science 2004
Dendritic Cells (DCs):5. bridging innate and adaptive immunity, by presenting Ag on their MHC II
priming adaptive immunity by activating CD4 T cells.6. Maturation and functional differentiation of conventional DCs are altered in
HCV infection, could possibly result in insufficient T cell priming and delayed HCV-specific T cell responses
Dolganiuc, A., et al. 2003. J. Immunol. 2003
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Antigen Presenting cells (e.g. DC)
Liver cells
HCV
CD8+ cytotoxic T cellTCR
CD8
MHC class I + peptide
Adaptive immunity: Key players
CD4+ helper cellTCR
B-cell
Antibodies
IFN-g
TH2 cytokines
IL-4, IL-10, IL-13
TH1 cytokines
(IFN-g, TNF-a)
1. Killing of infected cells
2. Neutralizing viral particles
3. Help
13Bowen D.G. and Walker CMNature 436, 946-952 (18 August 2005)
Patterns of Viral Replication and Immune responses in acute HCV
Transient control
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Mechanisms of CTL escape after mutation in cognate epitopes.
Bowen D and Walker CM, (2005). J. Exp. Med. 201:1709
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Patterns of Immune responses in acute ->chronic HCV infections
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Patterns of Immune responses in acute ->chronic HCV infections
Hepatic Fibrosis, The Main Pathology in HCV Induced Liver Injury
Bataller, R. Bremmer, DA. J Clin Invest, 2005
Hepatic Fibrosis, The Main Pathology in HCV Induced Liver Injury
Bataller, R. Bremmer, DA. J Clin Invest, 2005
Liver fibrosis:
Increased ECM depositionDecreased ECM degradationMMP (degrades), TIMP (inhibits MMP)
Decompensated Cirrhosis m
Compensated Cirrhosis m
Increasing Rate of Fibrosis
Time (Age)
Onset ofInfection
Progressive Fibrosis
HIV, HBV Co-InfectionHeavy Alcohol UseHemochromatosisWilson Diseaseα1 antitrypsin deficiency
Hepatic SteatosisAnd NASH
Acceleration of fibrosis
Progression of Fibrosis and CirrhosisIn HCV Infected Patients
40-86% of all HCV patients have hepatic steatosis.
Hepatic Steatosis and HCV
30-40% of HCV patients with steatosis do not have known risk factors such obesity, T2DM, etc…
Genotype dependent: more common andsevere in genotype 3.
Steatosis: abnormal retention of lipids within hepatocytes.
Hepatic Steatosis and HCVMetabolic VS Viral
Metabolic Type - genotype non 3
fatty liver is significantly reduced in sustained responders to antiviral treatment.
Steatosis α BMI
Viral-Type - genotype 3
Steatosis α Viral RNA
Possible Mechanisms of Steatosis:
1-Increased Lipogenesis
2-Decreased Lipid Oxidation
3-Decreased VLDL Secretion
.
Jensen M V et al. Am J Physiol Endocrinol Metab 2008;295:E1287-E1297
α-KGDH
Glucose
Fatty Acid Synthesis
Acetyl CoA Carboxylase (ACC)
Fatty Acid Synthase Complex (FAS)
Synthesis of Triacylglycerol
Acetyl CoA Carboxylase (ACC): The rate Limiting Enzyme
Substrate/product level regulation: activated with Citrate (Substrate), inhibited by Malonyl-CoA and Palmitoyl-CoA (Products)
Energy Level regulation: cAMP-PK and AMP-PK phosphorylates ACC and deactivates it. During fasting as ATP production declines AMP rises.
Hormonal regulation: Insulin (Feeding state hormone) activates ACC. Epinephrine and Glucagon (counter-regulatory, fasting state hormones) deactivates ACC.
Regulation of gene expression:
Cis Elemnent Trans Factor Effect
SRE SREBP Activates ACC and FAS
LXRE LXR Activated by Oxysterols
ChoRE ChoREBP Activates by high Cho Levels
Evidence of HCV Impact on Lipogenesis
Stimulation of SREBP by HCV GT2a (full ORF) and core/NS4B from GT3aWaris, G, et.al, Journal of Virology, 2007
NS2 of HCV H77 (GT1a) activates SREBP-1c results in increased FAS expression. Oem JK, et.al, J.Gen.Virol, 2007
NS4B from GT1b stimulates SREBP results in increased FAS expression. Park, CY, et.al, JBC, 2009
Transgenic mice with full length ORF of HCV GT1a stimulation of SREBP-1c and increase in transcription of FAS, SCD-1.
Lerat H, et.al, JBC, 2009Huh7 expressing HCV core from GT1b, increases ACC-1 activity and expression.
Fukasawa, M, et.al, Biol. Pharm Bulletin, 2006HCV GT3a and 1b core up-regulate FAS through SREBPs, GT3a>GT1b, Role of Phe 164 in activation of FAS.
Candice Jackel-Cram, et.al, Journal of Hepatology,2007Liver of CHC patients show increase in expression of LXRα, SREBP-1c and FAS.
Nakamuta, M. et.al, Int J Mol Med, 2009No Correlation between SREBP-1c and level of steatosis in liver of patients with HCV GT1 and 3
McPherson, S, et.al, Journal of Hepatology, 2008
Acetyl CoAMalonyl CoA-
Fatty Acid Oxidation Complex (FAS)
Evidence of HCV Impact on Fatty Acid Oxidation
Yasui K, et.al investigated the intrahepatic mRNA of genes important for lipid degradation in 100 HCV patients who lack metabolic factor for steatosis and compared the level between patients with steatosis vs non steatotic patients.
Yasui K, et.al, J Gastroenterol, 2009
Gene Symbol P value
PPARα 0.037
PPARγ 0.458
LXRα 0.001
RXRα 0.552
Gene Symbol P value
CPT1 0.204
SCAD <0.001
MCAD 0.059
LCAD 0.042
VLCAD 0.258
LBP 0.032
LCHAD 0.038
ACOX 0.040
CYP2E1 0.011
Nuclear ReceptorsFatty Acid Oxidation
VLDL Secretion
Evidence of HCV Impact on VLDL Secretion Pathway
Transgenic mice expressing HCV core have reduced MTP activity but not expressionPerlemuter, G, et.al, FASEB, 2002
Negative correlation between MTP mRNA&activity with HCV RNA levels in the liver of patients infected with HCV GT3 but not in non-GT3 HCV.
Mirandola S, et.al, Gastroenterology, 2006Hypobetalipoproteinemia in HCV GT3 patients and reversal after SVR.
Serfaty, L, et.al, Journal of Hepatology, 2001Hepatocellular fat accumulation and low serum cholesterol in patients infected with HCV-3a, reversal after SVR.
Hofer, H, et.al, Am J Gastroenterology, 2002
Why HCV inhibits MTP which is believe to be so critical for HCV life cycle????