Hepatitis C virus

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This page is about microbiologic aspects of the organism(s).  For clinical aspects of the disease, see Hepatitis C.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]


Hepatitis C infection is caused by the hepatitis C virus.

Hepatitis C Virus

Viral Characteristics

The 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]


  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 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.