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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. Introduction to Hepatitis C What is Hepatitis C? Transmission Symptoms Testing

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Biochemistry of Hepatitis C

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  1. Biochemistry of Hepatitis C Daye Jeong Joo-Oll Kim Ginyoung Lee Julia Wong PHM142 Fall 2013 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

  2. 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

  3. 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

  4. Diagnosis

  5. 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

  6. 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

  7. 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)

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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.

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