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Biochemistry of Hepatitis C. Daye Jeong Joo-Oll Kim Ginyoung Lee Julia Wong. PHM142 Fall 2013 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson. Outline. Introduction to Hepatitis C What is Hepatitis C? Transmission Symptoms Testing

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biochemistry of hepatitis c

Biochemistry of Hepatitis C

Daye Jeong

Joo-Oll Kim

Ginyoung Lee

Julia Wong

PHM142 Fall 2013

Coordinator: Dr. Jeffrey Henderson

Instructor: Dr. David Hampson

outline
Outline
  • Introduction to Hepatitis C
    • What is Hepatitis C?
    • Transmission
    • Symptoms
    • Testing
  • Transmission of Hepatitis C to the liver
  • How Hepatitis C affects the liver
  • Immune response
    • Adaptive
    • Innate
hepatitis c
Hepatitis C
  • What is Hepatitis C?
    • Contagious liver disease resulting from the Hepatitis C virus (HCV)
    • HCV is a small, enveloped, single-stranded positive-sense RNA virus
  • How it is transmitted
    • Blood-blood contact via an infected individual to a non-infected individual
    • IV drug use
    • Blood transfusions and organ transplants
    • Poorly sterilized medical equipment
    • Sexual intercourse
    • Infected mother during childbirth
  • Symptoms
    • Often asymptomatic, but can lead to cirrhosis (scarring of the liver), liver failure or liver cancer
    • Decreased appetite, nausea, muscle or joint pain, weight loss, vomiting, dark urine, abdominal pain, grey-coloured feces, jaundice
transmission pathway
Transmission Pathway

1. Delivery via blood

2. Binding

HCVgp (E1-E2)

Host Cell-Surface Molecules

(CD81, SR-BI, CLDN1, Occludin)

3. Endocytosis

4. Low pH-induced fusion of viral and cell membranes

5. Release of viral contents into cytosol

replication translation assembly and release
Replication, Translation, assembly and release

6. Replication, Translation

IRES-medicated translation of HCV ORF

Polyprotein precursor

7. Assembly inside of vesicles

8. Progeny virions bud, egress via cellular secretory pathway

9. Infect native cells

chronic hepatitis c virus infection hcv in liver
Chronic Hepatitis C Virus Infection (HCV) in Liver
  • Fibrosis
    • Fibrotic scarring due to increased extracellular deposition of matrix proteins & collagen
    • Intrahepatic lymphocytes contribute to sustained inflammation at the injured site
      • NF-κB: a central regulator of inflammatory responses
  • Cirrhosis
    • Results from unusual high activity of fibrogenesis compared to fibrosis degradation
    • Can lead to other complications
      • Jaundice
      • Variceal hemorrhage
      • Hepatic encephalopathy
      • Hepatocellular carcinoma (HCC)
chronic hepatitis c virus infection hcv in liver1
Chronic Hepatitis C Virus Infection (HCV) in Liver
  • Hepatocellular Carcinoma (HCC)
    • Results from chronic fibrosis and cirrhosis
    • Apoptosis of infected hepatocytes
      • Repeated cycles of cell death & regeneration – amplification of dormant cells with chromosomal damage.
  • Risk Factors
    • Age
    • Sex
    • Alcohol
    • Immunosuppressant
  • Liver Transplant
    • As a treatment method
immune response innate
Immune Response - Innate
  • Directly attacks the Killer T cells/ Dendritic cells
  • In liver, TLR/RLR receptors activated by adaptor mole. in hepatocytes recognizes pattern of HCV dsRNA
  • Infection 1) cleaves the adaptor mole.
  • Transcription of infected secretion

IFN – β

  • IFN – β induces JAK/STAT pathway
  • Pathway 2) inhibits translation of ISG mRNA

 Less production to IFN – α signaling innate immune response

immune response adaptive
Immune Response - Adaptive

RT

Successful

  • Antibodies blocks the binding of HCV

- T-CD4 recognize HCV / help T-CD8

  • T-CD8 produces antiviral cytokine

Failure

- Expression of inhibitory receptors

  • Suppression by regulatory T-Cell

 lack of CD4-CD8 communication

 CD8 dysfunction

  • Viral mutation
  • Hepatitis C is an RNA virus  MUTATION
summary slide
Summary Slide
  • Hepatitis C virus (HCV) is a small, enveloped, single-stranded positive-sense RNA virus
  • HCV is transmitted via blood-blood contact and can vary from being asymptomatic to developing liver failure
  • HCV antibody tests  tests for the presence of antibodies against the HCV virus
  • RNA/PCR test  tests for the presence of viral RNA
  • E1,E2 are HCV glycoproteins and form noncovalent heterodimers which binds to the host cell surface molecules. CD81, SR-BI, Claudin-1 and occludin are major co-receptors for the virus entry.
  • The virus enters into the cell by clathrin-mediated endocytosis and fuses into endosomal membrane in acidic early endosome.Viral genome and proteins are released into the cytosol for replication.
  • The replicated RNA and synthesized viral proteins assemble into progeny virions inside vesicles and can bud and egress through cellular secretory pathway for infecting more native cells in the body.
  • Chronic onset of Hepatitis C virus infection where most common diseases are due to chronic onset: fibrosis, cirrhosis and hepatocellular carcinoma(HCC)
  • Fibrotic scarring result from increased extracellular deposition of matrix proteins and collagen
  • Unusual high activity of fibrogenesis eventually lead to cirrhosis in which normal liver tissues are replaced by fibrotic scarred tissues.
  • Both fibrosis and cirrhosis eventually lead to hepatocellular carcinoma (HCC)
  • Age, sex, alcohol consumption, etc. are factors that are associated with HCV infection
  • The virus infect hepacytes’ gene to produce IFN- β which will hinder the production of IFN – α in neighboring hepacytes for signaling innate immune response
  • Suppressing regulatory T cells for T-CD4/T-CD8 cells communicate for antiviral activity, inhibitory receptor expression, and viral mutation hinders adaptive immunity
references
References
  • Castera, L. and Bedossa, P. (2011), How to assess liver fibrosis in chronic hepatitis C: serum markers or transient elastography vs. liver biopsy?. Liver International, 31: 13–17. doi: 10.1111/j.1478-3231.2010.02380.x
  • Centre for Disease, Control and Prevention ( 2013). Hepatitis C: Information on Testing & Diagnosis. Retrieved from http://www.cdc.gov/hepatitis/hcv/pdfs/hepctesting-diagnosis.pdf
  • Centre for Disease Control and Prevention (2013). Hepatitis C Information for Health Professionals. Retrieved from http://www.cdc.gov/hepatitis/hcv/labtesting.htm
  • Chen SL, Morgan TR. The Natural History of Hepatitis C Virus (HCV) Infection. Int J Med Sci 2006; 3(2):47-52. doi:10.7150/ijms.3.47. Available from http://www.medsci.org/v03p0047.htm
  • Eisentein M. (2011 June 8th). Vaccines: A moving target. Nature. Retrieved November 9th, 2013 from http://www.nature.com/nature/journal/v474/n7350_supp/full/474S16a.html?WT.ec_id=NATURE-20110609
  • Helle, F., & Dubuisson, J. (2008). Hepatitis C virus entry into host cells. Cellular and molecular life sciences, 65(1), 100-112.
  • Matsuzaki, K. (2009). Frontiers in Bioscience. 14: 2923-2934. doi: 10.2741/3423.
  • Meredith, L. W., Wilson, G. K., Fletcher, N. F., & McKeating, J. A. (2012). Hepatitis C virus entry: beyond receptors. Reviews in medical virology, 22(3), 182-193.
  • Neumann-Haefelin, C., & Thimme, R. (2013). Hepatitis C Virus: From Molecular Virology to Antiviral Therapy. p 244-247. Bartenshlager. Springer
  • Rehermann, B. (2009). Hepatitis C Virus Versus Innate and Adaptive Immune Responses: A Tale of Coevolution and Coexistence, J. Clin. Invest.119:1745–1754, doi:10.1172/JCI39133.
  • United States Department of Veterans Affairs (2013). Tests of hepatitis C. Retrieved from http://www.hepatitis.va.gov/patient/diagnosis/labtests-hepatitisC-tests.asp
  • von Hahn, T., & Rice, C. M. (2008). Hepatitis C virus entry. Journal of Biological Chemistry, 283(7), 3689-3693.