Mechanisms of Cell Entry of Hepatitis C Virus

  • Franco Dammacco
  • Vito Racanelli


The mechanisms by which HCV escapes the host immune response and gains entry into target cells are still largely unknown, although new methods in molecular virology are greatly contributing to the advancement of knowledge in this field. Model systems for the study of HCV cell entry include HCV-like particles, HCV pseudoparticles, cell-culture-produced HCV, and the tupaia animal model. Following the identification of tetraspanin CD81 with the use of recombinant E2 glycoprotein, additional cell-surface molecules have been shown to play a role as viral receptors on host cells, namely scavenger receptor (SR) BI, tight-junction proteins such as claudin-1 and occludin, glycosaminoglycans, and two membrane proteins of the C-type lectin family. It is possible that different circulating forms of HCV activate different pathways of cell entry. Nevertheless, lipoproteins and, in particular, LDL receptors are essential in virus cell entry. In the initial step, ApoB-associated HCV is bound and internalized through the interplay of virus-associated VLDL and SR-BI, which possibly implies the involvement of LDL receptors and glycosaminoglycans. In the next step, HCV binds to the SR-BI/CD81 complex and is transferred to the tight-junction proteins. Following clathrin-mediated endocytosis, the virus initiates fusion and releases its RNA genome into the cytosol. Further clarification of the biomolecular mechanisms underlying cellular entry of HCV will hopefully result in the identification of novel therapeutic compounds that selectively target entry.


Cell Entry Tetraspanin CD81 Biomolecular Mechanism Virus Cell Entry Entry Molecule 
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  1. 1.
    Houghton M (2009) The long and winding road leading to the identification of the hepatitis C virus. J Hepatol 51:939–948PubMedCrossRefGoogle Scholar
  2. 2.
    Alter MJ (1989) Non-A, non-B hepatitis: sorting through a diagnosis of exclusion. Ann Intern Med 110:583–585PubMedCrossRefGoogle Scholar
  3. 3.
    Choo QL, Kuo G, Weiner AJ et al (1989) Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244:359–362PubMedCrossRefGoogle Scholar
  4. 4.
    Fraser CS, Doudna J (2007) Structural and mechanistic insights into hepatitis C viral translation initiation. Nat Rev Microbiol 5:29–38PubMedCrossRefGoogle Scholar
  5. 5.
    Poenisch M, Bartenschlager R (2010) New insights into structure and replication of the hepatitis C virus and clinical implications. Semin Liver Dis 30:333–347PubMedCrossRefGoogle Scholar
  6. 6.
    Pileri P, Uematsu Y, Campagnoli S et al (1998) Binding of hepatitis C virus to CD81. Science 282:938–941PubMedCrossRefGoogle Scholar
  7. 7.
    Lohmann V, Körner F, Koch J et al (1999) Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285:110–113PubMedCrossRefGoogle Scholar
  8. 8.
    Bartenschlager R (2005) The hepatitis C virus replicon system: from basic research to clinical application. J Hepatol 43:210–216PubMedCrossRefGoogle Scholar
  9. 9.
    Burlone ME, Budkowska A (2009) Hepatitis C virus cell entry: role of lipoproteins and cellular receptors. J Gen Virol 90:1055–1070PubMedCrossRefGoogle Scholar
  10. 10.
    Shimizu YK, Iwamoto A, Hijikata M et al (1992) Evidence for in vitro replication of hepatitis C virus genome in a human T-cell line. Proc Natl Acad Sci USA 89:5477–5481PubMedCrossRefGoogle Scholar
  11. 11.
    von Hahn T, Rice CM (2008) Hepatitis C virus entry. J Biol Chem 283:3689–3693CrossRefGoogle Scholar
  12. 12.
    Scarselli E, Ansuini H, Cerino R et al (2002) The human scavenger receptor class B type I is a novel candidate receptor for the hepatitis C virus. EMBO J 21:5017–5025PubMedCrossRefGoogle Scholar
  13. 13.
    Barth H, Liang TJ, Baumert TF (2006) Hepatitis C virus entry: molecular biology and clinical implications. Hepatology 44:527–535PubMedCrossRefGoogle Scholar
  14. 14.
    Bartosch B, Dubuisson J, Cosset FL (2003) Infectious hepatitis C virus pseudo-particles containing functional E1-E2 envelope protein complexes. J Exp Med 197:633–642PubMedCrossRefGoogle Scholar
  15. 15.
    Lindenbach BD, Evans MJ, Syder AJ et al (2005) Complete replication of hepatitis C virus in cell culture. Science 309:623–626PubMedCrossRefGoogle Scholar
  16. 16.
    Wakita T, Pietschmann T, Kato T et al (2005) Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med 11:791–796PubMedCrossRefGoogle Scholar
  17. 17.
    Tong Y, Zhu Y, Xia X et al (2011) Tupaia CD81, SR-BI, claudin-1, and occludin support hepatitis C virus infection. J Virol 85:2793–2802PubMedCrossRefGoogle Scholar
  18. 18.
    Brass V, Moradpour D, Blum HE (2006) Molecular virology of hepatitis C virus (HCV): 2006 update. Int J Med Sci 3:29–34PubMedCrossRefGoogle Scholar
  19. 19.
    Zeisel MB, Fofana I, Fafi-Kremer S et al (2011) Hepatitis C virus entry into hepatocytes: molecular mechanisms and targets for antiviral therapies. J Hepatol 54:566–576PubMedCrossRefGoogle Scholar
  20. 20.
    Rocha-Perugini V, Montpellier C, Delgrange D et al (2008) The CD81 partner EWI-2wint inhibits hepatitis C virus entry. PLoS One 3:e1866PubMedCrossRefGoogle Scholar
  21. 21.
    Machida K, Cheng KT, Pavio N et al (2005) Hepatitis C virus E2-CD81 interaction induces hypermutation of the immunoglobulin gene in B cells. J Virol 79:8079–8089PubMedCrossRefGoogle Scholar
  22. 22.
    Zeisel MB, Koutsoudakis G, Schnober EK et al (2007) Scavenger receptor class B type I is a key host factor for hepatitis C virus infection required for an entry step closely linked to CD81. Hepatology 46:1722–1731PubMedCrossRefGoogle Scholar
  23. 23.
    Grove J, Huby T, Stamataki Z et al (2007) Scavenger receptor BI and BII expression levels modulate hepatitis C virus infectivity. J Virol 81:3162–3169PubMedCrossRefGoogle Scholar
  24. 24.
    Cai Z, Cai L, Jiang J et al (2007) Human serum amyloid A protein inhibits hepatitis C virus entry into cells. J Virol 81:6128–6133PubMedCrossRefGoogle Scholar
  25. 25.
    Murao K, Imachi H, Yu X et al (2008) Interferon alpha decreases expression of human scavenger receptor class BI, a possible HCV receptor in hepatocytes. Gut 57:664–667PubMedCrossRefGoogle Scholar
  26. 26.
    Evans MJ, von Hahn T, Tscherne DM et al (2007) Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry. Nature 446:801–805PubMedCrossRefGoogle Scholar
  27. 27.
    Liu S, Yang W, Shen L et al (2009) Tight junction proteins claudin-1 and occludin control hepatitis C virus entry and are downregulated during infection to prevent superinfection. J Virol 83:2011–2014PubMedCrossRefGoogle Scholar
  28. 28.
    Andréo U, Maillard P, Kalinina O et al (2007) Lipoprotein lipase mediates hepatitis C virus (HCV) cell entry and inhibits HCV infection. Cell Microbiol 9:2445–2456PubMedCrossRefGoogle Scholar
  29. 29.
    Gardner JP, Durso RJ, Arrigale RR et al (2003) L-SIGN (CD 209 L) is a liver-specific capture receptor for hepatitis C virus. Proc Natl Acad Sci USA 100:4498–4503PubMedCrossRefGoogle Scholar
  30. 30.
    Perrault M, Pécheur EI (2009) The hepatitis C virus and its hepatic environment: a toxic but finely tuned partnership. Biochem J 423:303–314PubMedCrossRefGoogle Scholar
  31. 31.
    Agnello V, Abel G, Elfahal M et al (1999) Hepatitis C virus and other flaviviridae viruses enter cells via low density lipoprotein receptor. Proc Natl Acad Sci USA 96:12766–12771PubMedCrossRefGoogle Scholar
  32. 32.
    Steinmann E, Whitfield T, Kallis S et al (2007) Antiviral effects of amantadine and iminosugar derivatives against hepatitis C virus. Hepatology 46:330–338PubMedCrossRefGoogle Scholar
  33. 33.
    Meuleman P, Leroux-Roels G (2008) The human liver-uPA-SCID mouse: a model for the evaluation of antiviral compounds against HBV and HCV. Antiviral Res 80:231–238PubMedCrossRefGoogle Scholar
  34. 34.
    Meuleman P, Hesselgesser J, Paulson M et al (2008) Anti-CD81 antibodies can prevent a hepatitis C virus infection in vivo. Hepatology 48:1761–1768PubMedCrossRefGoogle Scholar
  35. 35.
    Fafi-Kremer S, Fofana I, Soulier E et al (2010) Viral entry and escape from antibody-mediated neutralization influence hepatitis C virus reinfection in liver transplantation. J Exp Med 207:2019–2031PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2012

Authors and Affiliations

  1. 1.Department of Internal Medicine and Clinical OncologyUniversity of Bari Medical SchoolBariItaly

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