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Pathophysiology

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Handbook of Hepatitis C

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Abstract

In hepatitis C virus (HCV) infection liver damage is not due to direct effects of the virus; the immune response plays a primordial role in the pathophysiology of the disease.

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References

  1. Saito T, Owen DM, Jiang F, Marcotrigiano J, Gale M Jr. Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA. Nature. 2008;454:523–527.

    Google Scholar 

  2. Li K, Foy E, Ferreon JC, et al. Immune evasion by hepatitis C virus NS3/4A proteasemediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. Proc Natl Acad Sci U S A. 2005;102:2992–2997.

    Google Scholar 

  3. Foy E, Li K, Wang C, et al. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science. 2003;300:1145–1148.

    Google Scholar 

  4. Lin W, Kim SS, Yeung E, et al. Hepatitis C virus core protein blocks interferon signaling by interaction with the STAT1 SH2 domain. J Virol. 2006;80:9226–9235.

    Google Scholar 

  5. Bode JG, Ludwig S, Ehrhardt C, et al. IFN-alpha antagonistic activity of HCV core protein involves induction of suppressor of cytokine signaling-3. Faseb J. 2003;17:488–490.

    Google Scholar 

  6. Polyak SJ, Khabar KS, Paschal DM, et al. Hepatitis C virus nonstructural 5A protein induces interleukin-8, leading to partial inhibition of the interferon-induced antiviral response. J Virol. 2001;75:6095–6106.

    Google Scholar 

  7. Gale MJ Jr, Korth MJ, Tang NM, et al. Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein. Virology. 1997;230:217–227.

    Google Scholar 

  8. Taylor DR, Shi ST, Romano PR, Barber GN, Lai MM. Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein. Science. 1999;285:107–110.

    Google Scholar 

  9. Topham NJ, Hewitt EW. Natural killer cell cytotoxicity: how do they pull the trigger? Immunology. 2009;128:7–15.

    Google Scholar 

  10. Jinushi M, Takehara T, Tatsumi T, et al. Negative regulation of NK cell activities by inhibitory receptor CD94/NKG2A leads to altered NK cell-induced modulation of dendritic cell functions in chronic hepatitis C virus infection. J Immunol. 2004;173:6072–6081.

    Google Scholar 

  11. Tseng CT, Klimpel GR. Binding of the hepatitis C virus envelope protein E2 to CD81 inhibits natural killer cell functions. J Exp Med. 2002;195:43–49.

    Google Scholar 

  12. Dolganiuc A, Chang S, Kodys K, et al. Hepatitis C virus (HCV) core protein-induced, monocyte-mediated mechanisms of reduced IFN-alpha and plasmacytoid dendritic cell loss in chronic HCV infection. J Immunol. 2006;177:6758–6768.

    Google Scholar 

  13. Dolganiuc A, Kodys K, Kopasz A, et al. Hepatitis C virus core and nonstructural protein 3 proteins induce pro- and anti-inflammatory cytokines and inhibit dendritic cell differentiation. J Immunol. 2003;170:5615–5624.

    Google Scholar 

  14. Auffermann-Gretzinger S, Keeffe EB, Levy S. Impaired dendritic cell maturation in patients with chronic, but not resolved, hepatitis C virus infection. Blood. 2001;97:3171–3176.

    Google Scholar 

  15. Thimme R, Bukh J, Spangenberg HC, et al. Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease. Proc Natl Acad Sci U S A. 2002;99:15661–15668.

    Google Scholar 

  16. Logvinoff C, Major ME, Oldach D, et al. Neutralizing antibody response during acute and chronic hepatitis C virus infection. Proc Natl Acad Sci U S A. 2004;101:10149–10154.

    Google Scholar 

  17. Pestka JM, Zeisel MB, Blaser E, et al. Rapid induction of virus-neutralizing antibodies and viral clearance in a single-source outbreak of hepatitis C. Proc Natl Acad Sci U S A. 2007;104:6025–6030.

    Google Scholar 

  18. Semmo N, Lucas M, Krashias G, Lauer G, Chapel H, Klenerman P. Maintenance of HCVspecific T-cell responses in antibody-deficient patients a decade after early therapy. Blood. 2006;107:4570–4571.

    Google Scholar 

  19. Racanelli V, Frassanito MA, Leone P, et al. Antibody production and in vitro behavior of CD27-defined B-cell subsets: persistent hepatitis C virus infection changes the rules. J Virol. 2006;80:3923–3934.

    Google Scholar 

  20. Dammacco F, Sansonno D, Piccoli C, Racanelli V, D’Amore FP, Lauletta G. The lymphoid system in hepatitis C virus infection: autoimmunity, mixed cryoglobulinemia, and Overt B-cell malignancy. Semin Liver Dis. 2000;20:143–157.

    Google Scholar 

  21. Shoukry NH, Grakoui A, Houghton M, et al. Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection. J Exp Med. 2003;197:1645–1655.

    Google Scholar 

  22. Grakoui A, Shoukry NH, Woollard DJ, et al. HCV persistence and immune evasion in the absence of memory T cell help. Science. 2003;302:659–662.

    Google Scholar 

  23. Diepolder HM, Zachoval R, Hoffmann RM, et al. Possible mechanism involving T-lymphocyte response to non-structural protein 3 in viral clearance in acute hepatitis C virus infection. Lancet. 1995;346:1006–1007.

    Google Scholar 

  24. von Hahn T, Yoon JC, Alter H, et al. Hepatitis C virus continuously escapes from neutralizing antibody and T-cell responses during chronic infection in vivo. Gastroenterology. 2007;132:667–678.

    Google Scholar 

  25. Helle F, Goffard A, Morel V, et al. The neutralizing activity of anti-hepatitis C virus antibodies is modulated by specific glycans on the E2 envelope protein. J Virol. 2007;81:8101–8111.

    Google Scholar 

  26. Radziewicz H, Ibegbu CC, Hon H, et al. Impaired hepatitis C virus (HCV)-specific effector CD8+ T cells undergo massive apoptosis in the peripheral blood during acute HCV infection and in the liver during the chronic phase of infection. J Virol. 2008;82:9808–9822.

    Google Scholar 

  27. Nakamoto N, Kaplan DE, Coleclough J, et al. Functional restoration of HCV-specific CD8 T cells by PD-1 blockade is defined by PD-1 expression and compartmentalization. Gastroenterology. 2008;134:1927–1937.

    Google Scholar 

  28. Bengsch B, Spangenberg HC, Kersting N, et al. Analysis of CD127 and KLRG1 expression on hepatitis C virus-specific CD8+ T cells reveals the existence of different memory T-cell subsets in the peripheral blood and liver. J Virol. 2007;81:945–953.

    Google Scholar 

  29. Boettler T, Spangenberg HC, Neumann-Haefelin C, et al. T cells with a CD4+CD25+ regulatory phenotype suppress in vitro proliferation of virus-specific CD8+ T cells during chronic hepatitis C virus infection. J Virol. 2005;79:7860–7867.

    Google Scholar 

  30. Cabrera R, Tu Z, Xu Y, et al. An immunomodulatory role for CD4(+)CD25(+) regulatory T lymphocytes in hepatitis C virus infection. Hepatology. 2004;40:1062–1071.

    Google Scholar 

  31. D’Ambrosio R, Aghemo A, Rumi MG, et al. A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis. Hepatology. 2012;56:532–543.

    Google Scholar 

  32. Heydtmann M, Adams DH. Chemokines in the immunopathogenesis of hepatitis C infection. Hepatology. 2009;49:676–688.

    Google Scholar 

  33. Clement S, Pascarella S, Conzelmann S, Gonelle-Gispert C, Guilloux K, Negro F. The hepatitis C virus core protein indirectly induces alpha-smooth muscle actin expression in hepatic stellate cells via interleukin-8. J Hepatol. 2010:52:635–643.

    Google Scholar 

  34. Ming-Ju H, Yih-Shou H, Tzy-Yen C, Hui-Ling C. Hepatitis C virus E2 protein induce reactive oxygen species (ROS)-related fibrogenesis in the HSC-T6 hepatic stellate cell line. J Cell Biochem. 2011;112:233–243.

    Google Scholar 

  35. Rueger S, Bochud PY, Dufour JF, et al. Impact of common risk factors of fibrosis progression in chronic hepatitis C. Gut. 2014;64:1605–1615.

    Google Scholar 

  36. Asselah T, Rubbia-Brandt L, Marcellin P, Negro F. Steatosis in chronic hepatitis C: why does it really matter? Gut. 2006;55:123–130.

    Google Scholar 

  37. Rubbia-Brandt L, Quadri R, Abid K, et al. Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3. J Hepatol. 2000;33:106–115.

    Google Scholar 

  38. Leandro G, Mangia A, Hui J, et al. Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data. Gastroenterology. 2006;130:1636–1642.

    Google Scholar 

  39. Waris G, Felmlee DJ, Negro F, Siddiqui A. Hepatitis C virus induces proteolytic cleavage of sterol regulatory element binding proteins and stimulates their phosphorylation via oxidative stress. J Virol. 2007;81:8122–8130.

    Google Scholar 

  40. Perlemuter G, Sabile A, Letteron P, et al. Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis. Faseb J. 2002;16:185–194.

    Google Scholar 

  41. Mirandola S, Realdon S, Iqbal J, et al. Liver microsomal triglyceride transfer protein is involved in hepatitis C liver steatosis. Gastroenterology. 2006;130:1661–1669.

    Google Scholar 

  42. de Gottardi A, Pazienza V, Pugnale P, et al. Peroxisome proliferator-activated receptor-alpha and -gamma mRNA levels are reduced in chronic hepatitis C with steatosis and genotype 3 infection. Aliment Pharmacol Ther. 2006;23:107–114.

    Google Scholar 

  43. Yamaguchi A, Tazuma S, Nishioka T, et al. Hepatitis C virus core protein modulates fatty acid metabolism and thereby causes lipid accumulation in the liver. Dig Dis Sci. 2005;50:1361–1371.

    Google Scholar 

  44. Dharancy S, Malapel M, Perlemuter G, et al. Impaired expression of the peroxisome proliferator-activated receptor alpha during hepatitis C virus infection. Gastroenterology. 2005;128:334–342.

    Google Scholar 

  45. Clement S, Peyrou M, Sanchez-Pareja A, et al. Down-regulation of phosphatase and tensin homolog by hepatitis C virus core 3a in hepatocytes triggers the formation of large lipid droplets. Hepatology. 2011;54:38–49.

    Google Scholar 

  46. Herker E, Ott M. Unique ties between hepatitis C virus replication and intracellular lipids. Trends Endocrinol Metab. 2011;22:241–248.

    Google Scholar 

  47. GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385:117–171.

    Google Scholar 

  48. Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol. 2006;45:529–538.

    Google Scholar 

  49. Simonetti RG, Camma C, Fiorello F, Politi F, D’Amico G, Pagliaro L. Hepatocellular carcinoma. A worldwide problem and the major risk factors. Dig Dis Sci. 1991;36:962–972.

    Google Scholar 

  50. Hung CH, Wang JH, Hu TH, et al. Insulin resistance is associated with hepatocellular carcinoma in chronic hepatitis C infection. World J Gastroenterol. 2010;16:2265–2271.

    Google Scholar 

  51. Kuske L, Mensen A, Mullhaupt B, et al. Characteristics of patients with chronic hepatitis C who develop hepatocellular carcinoma. Swiss Med Wkly. 2012;142:w13651.

    Google Scholar 

  52. Ohata K, Hamasaki K, Toriyama K, et al. Hepatic steatosis is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C virus infection. Cancer. 2003;97:3036–3043.

    Google Scholar 

  53. Kurosaki M, Hosokawa T, Matsunaga K, et al. Hepatic steatosis in chronic hepatitis C is a significant risk factor for developing hepatocellular carcinoma independent of age, sex, obesity, fibrosis stage and response to interferon therapy. Hepatol Res. 2010;40:870–877.

    Google Scholar 

  54. Hayashi J, Aoki H, Kajino K, Moriyama M, Arakawa Y, Hino O. Hepatitis C virus core protein activates the MAPK/ERK cascade synergistically with tumor promoter TPA, but not with epidermal growth factor or transforming growth factor alpha. Hepatology. 2000;32:958–961.

    Google Scholar 

  55. Liu J, Ding X, Tang J, et al. Enhancement of canonical Wnt/beta-catenin signaling activity by HCV core protein promotes cell growth of hepatocellular carcinoma cells. PLoS One. 2011;6:e27496.

    Google Scholar 

  56. Taniguchi H, Kato N, Otsuka M, et al. Hepatitis C virus core protein upregulates transforming growth factor-beta 1 transcription. J Med Virol. 2004;72:52–59.

    Google Scholar 

  57. Higgs MR, Lerat H, Pawlotsky JM. Hepatitis C virus-induced activation of β-catenin promotes c-Myc expression and a cascade of pro-carcinogenetic events. Oncogene. 2013;32:4683–4693.

    Google Scholar 

  58. Hussain SP, Schwank J, Staib F, Wang XW, Harris CC. TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer. Oncogene. 2007;26:2166–2176.

    Google Scholar 

  59. Nishimura T, Kohara M, Izumi K, et al. Hepatitis C virus impairs p53 via persistent overexpression of 3beta-hydroxysterol Delta24-reductase. J Biol Chem. 2009;284:36442–36452.

    Google Scholar 

  60. Munakata T, Nakamura M, Liang Y, Li K, Lemon SM. Down-regulation of the retinoblastoma tumor suppressor by the hepatitis C virus NS5B RNA-dependent RNA polymerase. Proc Natl Acad Sci U S A. 2005;102:18159–18164.

    Google Scholar 

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Author information

Authors and Affiliations

  1. Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, USA

    Nicolas Goossens

  2. Department of Clinical Pathology, Faculty of Medicine, Geneva University Hospitals, Geneva, Geneve, Switzerland

    Sophie Clément

  3. Geneva University Hospitals, Geneva, Geneve, Switzerland

    Francesco Negro

Authors
  1. Nicolas Goossens
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  2. Sophie Clément
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  3. Francesco Negro
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Editor information

Editors and Affiliations

  1. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA

    Nicolas Goossens

  2. University Hospitals and Faculty of Medi, Clinical Pathology, Geneva, Geneve, Switzerland

    Sophie Clément

  3. Division of Gastroenterology and Hepatol, Geneva University Hospital, Geneva 14, Geneve, Switzerland

    Francesco Negro

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Goossens, N., Clément, S., Negro, F. (2016). Pathophysiology. In: Goossens, N., Clément, S., Negro, F. (eds) Handbook of Hepatitis C . Adis, Cham. https://doi.org/10.1007/978-3-319-28053-0_4

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  • DOI: https://doi.org/10.1007/978-3-319-28053-0_4

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  • Publisher Name: Adis, Cham

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