Hepatitis C pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-In-Chief: Yazan Daaboul; Serge Korjian

Overview

Hepatitis C virus (HCV) is a member of the genus Hepacivirus that belongs to the Flaviviridae family. It is an enveloped, single-stranded RNA virus that measures approximately 60 nm in diameter. The virus enters the cell using E1 and E2 envelope proteins. HCV RNA acts as template for the production of new proteins by translational, co-translational, and post-translational processes. These mechanisms lead to the synthesis of 10 proteins, 3 of which are structural and 7 of which are non-structural. In isolated acute HCV infection, the host immune system causes secretion of interferon-alpha and activation of natural killer cells, along with proper activation of adaptive immune cells. Chronic HCV is characterized by the impairment of these mechanisms. Eventually, chronic HCV infection leads to local inflammation and fibrogenesis causing hepatic injury and cirrhosis. Hepatocellular carcinoma, a known complication of chronic HCV infection, arises in cases of cirrhosis; the role of oncogenic proteins of HCV in the pathogenesis of hepatocellular carcinoma is yet to be elucidated.

Characteristics

Hepatitis C virus (HCV) is a member of the genus Hepacivirus that belongs to the Flaviviridae family. It is an enveloped, single-stranded RNA virus that measures approximately 60 nm in diameter.

Mode of Transmission

HCV is primarily transmitted by blood. Exposure to blood is observed primarily in healthcare settings, such as in blood transfusions, surgical procedures, needle injuries, and hemodialysis. Also, the role of intravenous drug use has recently emerged as a great risk for viral transmission after the relatively successful control of nosocomial HCV transmission.[1]

Life Cycle

Humans are considered the only natural hosts for HCV. The full life cycle of the virus is poorly understood due to difficulty to culture in vitro. The expression of E1-E2, two important envelope glycoprotein complexes, on the surface of HCV allows the virus to interact with host-cell molecules (glycosaminoglycans) by acting as ligands for cellular receptors, such as tetraspanin CD81, scavenger receptor class B type I (SR-BI), and mannose binding lectins DC-SIGN and L-SIGN. This interaction is believed to have a crucial role in cell recognition and cellular tropism.[2][3][4][5][6][7][8][9][10] The exact mechanism by which viral genome enters the host cell is poorly understood, but it is believed to be via receptor-mediated endocytosis. Then envelope glycoproteins utilize pH-dependent mechanisms to mediate fusion of the viral envelope using endosomal membrane.[6][7] As soon as it is released into the cytoplasm, the viral nucleocapsid uncoats by unknown mechanisms.

Template HCV RNA allows viral replication to take place and protein synthesis is thus facilitated. Cap-independent protein translation takes place when ribosomal 40S subunit binds to internal ribosome entry site (IRES).[11] IRES is a stem-loop structure that is located at the 5' untranslated region (UTR) of the virus and the initial 30-40 nucleotides of the viral core-encoding region.[11] Nonetheless, full polyprotein translation also requires the use of 80S ribosomes and the viral 3' UTR, both of which presumably play a role in regulation of the translational process.[12]

Translation is accompanied by co-translational processes and followed by post-translational processes; all of which yield a total of 10 mature proteins.[13]

The following proteins are produced:

Structural Proteins:

  • Core (C) protein[12]
  • Envelope 1 (E1) glycoprotein[12]
  • Envelope 2 (E2) glycoprotein[12]

C, E1, and E2 are separated from the remaining 7 non-structural proteins by the activity of p7, a small membrane polypeptide that belongs to viroporin family.[12] The 3 proteins are released by the activity of signal peptidases mediated by the host cell.

Non-Structural (NS) Proteins:

  • p7: Separation of structural from non-structural proteins and possible formation of ion channel[12][14]

Non-structural proteins NS3 to NS5B play an important role in the formation of a replication complex that includes an intracellular "membranous web", at least partially derived from host endoplasmic reticulum.[15] The replication complex is responsible for synthesis template negative-strand RNA and consequent synthesis of its positive-strand counterpart. These RNA molecules are then enclosed in new virions.

Formation of Nucleocapsid and Envelope

New HCV nucleocapsid is formed by the action of core protein C along with viral genomic positive-strand RNA.[12] The envelope of the newly formed nucleocapsid is later formed by budding action into the lumen of the endoplasmic reticulum. Nonetheless, envelope glycoproteins do not yet mature early on at this stage. When new virions are exported outside the host cell, via cellular secretory mechanisms, glycoproteins of the envelope finally mature.[12]

HCV Clearance and Persistence

Acute viral infection and HCV replication triggers the activation of the host immune response, first by secretion of type I interferon-alpha (IFN-alpha) and activation of natural killer (NK) cell. Nonetheless, secretion of endogenous IFN does not seem to effectively inhibit HCV replication.[16][17][18]

HCV proteins seem to play an inhibitory role on IFN-alpha effectors, such as IFN regulatory factor-3 (IRF-3), double stranded RNA-dependent protein kinase (PKR), and Jak-Stat pathway.[19][20][21] More importantly, chronic carriage of HCV is associated with impaired activation of NK cells despite IFN-alpha secretion. It is believed that cross-linking of CD81 and envelope protein E2 of the virus is a key mechanism by which NK cells are inactivated and INF-gamma by these cells is failed to be produced.[12]

It is confirmed that activation of IFN-gamma is a pre-requisite for the appropriate clearance of HCV. When activation occurs appropriately, antibodies start to form 7-31 weeks later.[22][23][24][25] While most epitopes for antibodies have not been discovered yet, hypervariable region 1 (HVR1) of the E2 envelope glycoprotein was found to be a target by anti-HVR1 antibodies. Antibodies play a role in clearing the virus from the host. It is currently unknown whether "escape" mechanisms are present in HCV that favor persistent HCV infection despite an adequate antibody response.[22][23][24][25]

Similarly, activation of CD4+ and CD8+ T-cell response is required for viral clearance. This cellular response allows long-term immunity against HCV.[26] Studies also proved that delayed or inadequate activation of T-cell response is associated with persistence of infection. It is not known why T-cell response may fail in response to acute infection, but it is hypothesized that persistence might be related to viral inhibition of T-cell maturation, defective dendritic cells, and/or failure of interleukin (IL) 12 activation.[26][27][28][29][30][31]

Liver Injury and Cirrhosis, and Hepatocellular Carcinoma

HCV is directly associated with hepatic steatosis, which is fat accumulation in the liver. It seems that core proteins may play a role in regulating lipid accumulation in hepatocytes, contributing to steatosis. However, steatosis is not observed in all genotypes of HCV infection, it is classically described in genotype 3, which perhaps is the only genotype that has a direct role in the development of steatosis irrespective of alcohol or metabolic elements. Apart from steatosis, HCV per se has not been shown to have damaging effects on hepatocytes. The viral burden also does not seem to be directly related to the extent of liver injury.[32][33][34][35][36][37][38]

In chronic hepatitis C infections, local immune response lead to portal lymphoid infiltration and chronic inflammation that lead to bridging necrosis and degenerative lobular lesions.[12] Hepatic injury is directly associated with the degree of Th1 cytokine expression. Adaptive immune system, namely cytotoxic T-cell response, injures infected cells, as well as bystander cells. Nonetheless, it has not been confirmed whether increased number of cytotoxic T cells is associated with extent of liver injury.

Chronic inflammation ultimately leads to fibrogenesis due to deposition extracellular matrix elements in hepatic parenchyma. It is unknown whether viral components are directly responsible in the particular mechanism of hepatic cirrhosis in chronic HCV infection; although cirrhosis is definitely worsened in HCV patients who are also exposed to other risk factors, such as alcohol, obesity, and HIV.[12]

Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) occurs following chronic HCV infection complicated by liver cirrhosis. The true role of HCV components in the development of HCC is poorly understood. Pinpointing which viral protein is directly related to carcinogenesis has been difficult, but studies have shown that NS3, NS4B, and NS5A all have oncogenic properties.[1][39][40][41][42]

Histology

Click on the arrow to view the pathologic findings in viral hepatitis: {{#ev:youtube|_hXvbpSxFZw}}

References

  1. ↑ 1.0 1.1 National Institutes of Health (2002). "National Institutes of Health Consensus Development Conference Statement: Management of hepatitis C: 2002--June 10-12, 2002". Hepatology. 36 (5 Suppl 1): S3–20. doi:10.1053/jhep.2002.37117. PMID 12407572.
  2. ↑ Op De Beeck A, Cocquerel L, Dubuisson J (2001). "Biogenesis of hepatitis C virus envelope glycoproteins". J Gen Virol. 82 (Pt 11): 2589–95. PMID 11602769.
  3. ↑ Penin F, Combet C, Germanidis G, Frainais PO, Deléage G, Pawlotsky JM (2001). "Conservation of the conformation and positive charges of hepatitis C virus E2 envelope glycoprotein hypervariable region 1 points to a role in cell attachment". J Virol. 75 (12): 5703–10. doi:10.1128/JVI.75.12.5703-5710.2001. PMC 114285. PMID 11356980.
  4. ↑ Barth H, Schafer C, Adah MI, Zhang F, Linhardt RJ, Toyoda H; et al. (2003). "Cellular binding of hepatitis C virus envelope glycoprotein E2 requires cell surface heparan sulfate". J Biol Chem. 278 (42): 41003–12. doi:10.1074/jbc.M302267200. PMID 12867431.
  5. ↑ Pileri P, Uematsu Y, Campagnoli S, Galli G, Falugi F, Petracca R; et al. (1998). "Binding of hepatitis C virus to CD81". Science. 282 (5390): 938–41. PMID 9794763.
  6. ↑ 6.0 6.1 Bartosch B, Vitelli A, Granier C, Goujon C, Dubuisson J, Pascale S; et al. (2003). "Cell entry of hepatitis C virus requires a set of co-receptors that include the CD81 tetraspanin and the SR-B1 scavenger receptor". J Biol Chem. 278 (43): 41624–30. doi:10.1074/jbc.M305289200. PMID 12913001.
  7. ↑ 7.0 7.1 Hsu M, Zhang J, Flint M, Logvinoff C, Cheng-Mayer C, Rice CM; et al. (2003). "Hepatitis C virus glycoproteins mediate pH-dependent cell entry of pseudotyped retroviral particles". Proc Natl Acad Sci U S A. 100 (12): 7271–6. doi:10.1073/pnas.0832180100. PMC 165865. PMID 12761383.
  8. ↑ Scarselli E, Ansuini H, Cerino R, Roccasecca RM, Acali S, Filocamo G; et al. (2002). "The human scavenger receptor class B type I is a novel candidate receptor for the hepatitis C virus". EMBO J. 21 (19): 5017–25. PMC 129051. PMID 12356718.
  9. ↑ Lozach PY, Lortat-Jacob H, de Lacroix de Lavalette A, Staropoli I, Foung S, Amara A; et al. (2003). "DC-SIGN and L-SIGN are high affinity binding receptors for hepatitis C virus glycoprotein E2". J Biol Chem. 278 (22): 20358–66. doi:10.1074/jbc.M301284200. PMID 12609975.
  10. ↑ Pöhlmann S, Zhang J, Baribaud F, Chen Z, Leslie GJ, Lin G; et al. (2003). "Hepatitis C virus glycoproteins interact with DC-SIGN and DC-SIGNR". J Virol. 77 (7): 4070–80. PMC 150620. PMID 12634366.
  11. ↑ 11.0 11.1 Tsukiyama-Kohara K, Iizuka N, Kohara M, Nomoto A (1992). "Internal ribosome entry site within hepatitis C virus RNA". J Virol. 66 (3): 1476–83. PMC 240872. PMID 1310759.
  12. ↑ 12.00 12.01 12.02 12.03 12.04 12.05 12.06 12.07 12.08 12.09 12.10 12.11 12.12 12.13 12.14 12.15 12.16 Pawlotsky JM (2004). "Pathophysiology of hepatitis C virus infection and related liver disease". Trends Microbiol. 12 (2): 96–102. doi:10.1016/j.tim.2003.12.005. PMID 15036326.
  13. ↑ Grakoui A, Wychowski C, Lin C, Feinstone SM, Rice CM (1993). "Expression and identification of hepatitis C virus polyprotein cleavage products". J Virol. 67 (3): 1385–95. PMC 237508. PMID 7679746.
  14. ↑ 14.0 14.1 14.2 14.3 14.4 14.5 14.6 Penin F, Dubuisson J, Rey FA, Moradpour D, Pawlotsky JM (2004). "Structural biology of hepatitis C virus". Hepatology. 39 (1): 5–19. doi:10.1002/hep.20032. PMID 14752815.
  15. ↑ Egger D, Wölk B, Gosert R, Bianchi L, Blum HE, Moradpour D; et al. (2002). "Expression of hepatitis C virus proteins induces distinct membrane alterations including a candidate viral replication complex". J Virol. 76 (12): 5974–84. PMC 136238. PMID 12021330.
  16. ↑ Thimme R, Oldach D, Chang KM, Steiger C, Ray SC, Chisari FV (2001). "Determinants of viral clearance and persistence during acute hepatitis C virus infection". J Exp Med. 194 (10): 1395–406. PMC 2193681. PMID 11714747.
  17. ↑ Thimme R, Bukh J, Spangenberg HC, Wieland S, Pemberton J, Steiger C; et al. (2002). "Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease". Proc Natl Acad Sci U S A. 99 (24): 15661–8. doi:10.1073/pnas.202608299. PMC 137773. PMID 12441397.
  18. ↑ Su AI, Pezacki JP, Wodicka L, Brideau AD, Supekova L, Thimme R; et al. (2002). "Genomic analysis of the host response to hepatitis C virus infection". Proc Natl Acad Sci U S A. 99 (24): 15669–74. doi:10.1073/pnas.202608199. PMC 137774. PMID 12441396.
  19. ↑ Katze MG, He Y, Gale M (2002). "Viruses and interferon: a fight for supremacy". Nat Rev Immunol. 2 (9): 675–87. doi:10.1038/nri888. PMID 12209136.
  20. ↑ Foy E, Li K, Wang C, Sumpter R, Ikeda M, Lemon SM; et al. (2003). "Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease". Science. 300 (5622): 1145–8. doi:10.1126/science.1082604. PMID 12702807.
  21. ↑ Blindenbacher A, Duong FH, Hunziker L, Stutvoet ST, Wang X, Terracciano L; et al. (2003). "Expression of hepatitis c virus proteins inhibits interferon alpha signaling in the liver of transgenic mice". Gastroenterology. 124 (5): 1465–75. PMID 12730885.
  22. ↑ 22.0 22.1 Farci P, Alter HJ, Wong DC, Miller RH, Govindarajan S, Engle R; et al. (1994). "Prevention of hepatitis C virus infection in chimpanzees after antibody-mediated in vitro neutralization". Proc Natl Acad Sci U S A. 91 (16): 7792–6. PMC 44488. PMID 7519785.
  23. ↑ 23.0 23.1 Shimizu YK, Igarashi H, Kiyohara T, Cabezon T, Farci P, Purcell RH; et al. (1996). "A hyperimmune serum against a synthetic peptide corresponding to the hypervariable region 1 of hepatitis C virus can prevent viral infection in cell cultures". Virology. 223 (2): 409–12. doi:10.1006/viro.1996.0497. PMID 8806581.
  24. ↑ 24.0 24.1 Bartosch B, Dubuisson J, Cosset FL (2003). "Infectious hepatitis C virus pseudo-particles containing functional E1-E2 envelope protein complexes". J Exp Med. 197 (5): 633–42. PMC 2193821. PMID 12615904.
  25. ↑ 25.0 25.1 Puntoriero G, Meola A, Lahm A, Zucchelli S, Ercole BB, Tafi R; et al. (1998). "Towards a solution for hepatitis C virus hypervariability: mimotopes of the hypervariable region 1 can induce antibodies cross-reacting with a large number of viral variants". EMBO J. 17 (13): 3521–33. doi:10.1093/emboj/17.13.3521. PMC 1170689. PMID 9649423.
  26. ↑ 26.0 26.1 Bertoletti A, Ferrari C (2003). "Kinetics of the immune response during HBV and HCV infection". Hepatology. 38 (1): 4–13. doi:10.1053/jhep.2003.50310. PMID 12829979.
  27. ↑ Bain C, Fatmi A, Zoulim F, Zarski JP, Trépo C, Inchauspé G (2001). "Impaired allostimulatory function of dendritic cells in chronic hepatitis C infection". Gastroenterology. 120 (2): 512–24. PMID 11159892.
  28. ↑ Wedemeyer H, He XS, Nascimbeni M, Davis AR, Greenberg HB, Hoofnagle JH; et al. (2002). "Impaired effector function of hepatitis C virus-specific CD8+ T cells in chronic hepatitis C virus infection". J Immunol. 169 (6): 3447–58. PMID 12218168.
  29. ↑ Lechner F, Wong DK, Dunbar PR, Chapman R, Chung RT, Dohrenwend P; et al. (2000). "Analysis of successful immune responses in persons infected with hepatitis C virus". J Exp Med. 191 (9): 1499–512. PMC 2213430. PMID 10790425.
  30. ↑ Appay V, Dunbar PR, Callan M, Klenerman P, Gillespie GM, Papagno L; et al. (2002). "Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections". Nat Med. 8 (4): 379–85. doi:10.1038/nm0402-379. PMID 11927944.
  31. ↑ Kittlesen DJ, Chianese-Bullock KA, Yao ZQ, Braciale TJ, Hahn YS (2000). "Interaction between complement receptor gC1qR and hepatitis C virus core protein inhibits T-lymphocyte proliferation". J Clin Invest. 106 (10): 1239–49. doi:10.1172/JCI10323. PMC 381434. PMID 11086025.
  32. ↑ Poynard T, Ratziu V, McHutchison J, Manns M, Goodman Z, Zeuzem S; et al. (2003). "Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C." Hepatology. 38 (1): 75–85. doi:10.1053/jhep.2003.50267. PMID 12829989.
  33. ↑ Barba G, Harper F, Harada T, Kohara M, Goulinet S, Matsuura Y; et al. (1997). "Hepatitis C virus core protein shows a cytoplasmic localization and associates to cellular lipid storage droplets". Proc Natl Acad Sci U S A. 94 (4): 1200–5. PMC 19768. PMID 9037030.
  34. ↑ Rubbia-Brandt L, Quadri R, Abid K, Giostra E, Malé PJ, Mentha G; et al. (2000). "Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3". J Hepatol. 33 (1): 106–15. PMID 10905593.
  35. ↑ Serfaty L, Andreani T, Giral P, Carbonell N, Chazouillères O, Poupon R (2001). "Hepatitis C virus induced hypobetalipoproteinemia: a possible mechanism for steatosis in chronic hepatitis C." J Hepatol. 34 (3): 428–34. PMID 11322205.
  36. ↑ Castéra L, Hézode C, Roudot-Thoraval F, Bastie A, Zafrani ES, Pawlotsky JM; et al. (2003). "Worsening of steatosis is an independent factor of fibrosis progression in untreated patients with chronic hepatitis C and paired liver biopsies". Gut. 52 (2): 288–92. PMC 1774979. PMID 12524415.
  37. ↑ Sulkowski MS, Thomas DL (2003). "Hepatitis C in the HIV-Infected Person". Ann Intern Med. 138 (3): 197–207. PMID 12558359.
  38. ↑ Pol S, Vallet-Pichard A, Fontaine H, Lebray P (2002). "HCV infection and hemodialysis". Semin Nephrol. 22 (4): 331–9. PMID 12118398.
  39. ↑ Ray RB, Lagging LM, Meyer K, Ray R (1996). "Hepatitis C virus core protein cooperates with ras and transforms primary rat embryo fibroblasts to tumorigenic phenotype". J Virol. 70 (7): 4438–43. PMC 190377. PMID 8676467.
  40. ↑ Sakamuro D, Furukawa T, Takegami T (1995). "Hepatitis C virus nonstructural protein NS3 transforms NIH 3T3 cells". J Virol. 69 (6): 3893–6. PMC 189112. PMID 7745741.
  41. ↑ Park JS, Yang JM, Min MK (2000). "Hepatitis C virus nonstructural protein NS4B transforms NIH3T3 cells in cooperation with the Ha-ras oncogene". Biochem Biophys Res Commun. 267 (2): 581–7. doi:10.1006/bbrc.1999.1999. PMID 10631105.
  42. ↑ Ghosh AK, Steele R, Meyer K, Ray R, Ray RB (1999). "Hepatitis C virus NS5A protein modulates cell cycle regulatory genes and promotes cell growth". J Gen Virol. 80 ( Pt 5): 1179–83. PMID 10355764.

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