Journal of Biosciences

, Volume 28, Issue 3, pp 287–304

The hepatitis C virus persistence: how to evade the immune system?

  • Nicole Pavio
  • Michael M. C. Lai


Hepatitis C virus (HCV) is an emerging virus of medical importance. A majority of HCV infections become chronic and lead to chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. HCV usually induces robust immune responses, but it frequently escapes the immune defense to establish persistent infection. The fact that HCV exists as an evolving quasispecies plays an important role in the selection of escape mutants. Furthermore, several viral proteins interfere with cellular functions, in particular, those involved in the immune response of the host. Several HCV proteins also modulate cell signalling through interaction with different effectors involved in cell proliferation and apoptosis, or in the interferon-signalling pathway. In addition, HCV infects immune cells such as B and T cells, and thus affects their normal functions. These various strategies used by HCV to counter the immune response of the host are reviewed here. A better understanding of these mechanisms would help design new therapeutic targets.


Cell signalling hepatitis C virus immune system 

Abbreviations used


Cytotoxic T lymphocytes


dendritic cells


hepatitis C virus


hypervariable region 1


internal ribsomal entry site


LDL receptor


lymphotoxin β-receptor


mixed cryoglobulinemia


major histocompatibility complex class-I


natural killer


neutralizing of binding




open reading frame


peripheral blood mononuclear cells






tumour necrosis factor


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Agnello V, Abel G, Elfahal M, Knight G B and Zhang Q X 1999 Hepatitis C virus and other flaviviridae viruses enter cells via low density lipoprotein receptor;Proc. Natl. Acad. Sci. USA 96 12766–12771PubMedGoogle Scholar
  2. Ali N and Siddiqui A 1995 Interaction of polypyrimidine tract-binding protein with the 5′ noncoding region of the hepatitis C virus RNA genome and its functional requirement in internal initiation of translation;J. Virol. 69 6367–6375PubMedGoogle Scholar
  3. Ali N and Siddiqui A 1997 The La antigen binds 5′ noncoding region of the hepatitis C virus RNA in the context of the initiator AUG codon and stimulates internal ribosome entry site-mediated translation;Proc. Natl. Acad. Sci. USA 94 2249–2254PubMedGoogle Scholar
  4. Araya V, Rakela J and Wright T 1997 Hepatitis C after orthotopic liver transplantation;Gastroenterology 112 575–582PubMedGoogle Scholar
  5. Arima N, Kao C Y, Licht T, Padmanabhan R, Sasaguri Y and Padmanabhan R 2001 Modulation of cell growth by the hepatitis C virus nonstructural protein NS5A;J. Biol. Chem. 276 12675–12684PubMedGoogle Scholar
  6. Auffermann-Gretzinger S, Keeffe E B and Levy S 2001 Impaired dendritic cell maturation in patients with chronic, but not resolved, hepatitis C virus infection;Blood 97 3171–3176PubMedGoogle Scholar
  7. Bain C, Fatmi A, Zoulim F, Zarski J P, Trepo C and Inchauspe G 2001 Impaired allostimulatory function of dendritic cells in chronic hepatitis C infection;Gastroenterology 120 512–524PubMedGoogle Scholar
  8. Barba G, Harper F, Harada T, Kohara M, Goulinet S, Matsuura Y, Eder G, Schaff Z, Chapman M J, Miyamura T and Brechot C 1997 Hepatitis C virus core protein shows a cytoplasmic localization and associates to cellular lipid storage droplets;Proc. Natl. Acad. Sci. USA 94 1200–1205PubMedGoogle Scholar
  9. Baumert T F, Ito S, Wong D T and Liang T J 1998 Hepatitis C virus structural proteins assemble into viruslike particles in insect cells;J. Virol. 72 3827–3836PubMedGoogle Scholar
  10. Bell D, Young J W and Banchereau J 1999 Dendritic cells;Adv. Immunol. 72 255–324PubMedGoogle Scholar
  11. Bergqvist A and Rice C M 2001 Transcriptional activation of the interleukin-2 promoter by hepatitis C virus core protein;J. Virol. 75 772–781PubMedGoogle Scholar
  12. Biro L, Varga L, Par A, Nemesanszky E, Csepregi A, Telegdy L, Ibranyi E, David K, Horvath G, Szentgyorgyi L, Nagy I, Dalmi L, Abonyi M, Fust G and Horanyi M 2000 Changes in the acute phase complement component and IL-6 levels in patients with chronic hepatitis C receiving interferon alpha-2b;Immunol. Lett. 72 69–744PubMedGoogle Scholar
  13. Blight K J, Kolykhalov A A and Rice C M 2000 Efficient initiation of HCV RNA replication in cell culture;Science 290 1972–1974PubMedGoogle Scholar
  14. Booth J C, Kumar U, Webster D, Monjardino J and Thomas H C 1998 Comparison of the rate of sequence variation in the hypervariable region of E2/NS1 region of hepatitis C virus in normal and hypogammaglobulinemic patients;Hepatology 11 223–227Google Scholar
  15. Borowski P, Oehlmann K, Heiland M and Laufs R 1997 Non-structural protein 3 of hepatitis C virus blocks the distribution of the free catalytic subunit of cyclic AMP-dependent protein kinase;J. Virol. 71 2838–2843PubMedGoogle Scholar
  16. Boyer J C and Haenni A L 1994 Infectious transcripts and cDNA clones of RNA viruses;Virology 198 415–426PubMedGoogle Scholar
  17. Bronowicki J P, Loriot M A, Thiers V, Grignon Y, Zignego A L and Brechot C 1998 Hepatitis C virus persistence in human hematopoietic cells injected into SCID mice;Hepatology 28 211–218PubMedGoogle Scholar
  18. Brown E A, Zhang H, Ping L H and Lemon S M 1992 Secondary structure of the 5′ nontranslated regions of hepatitis C virus and pestivirus genomic RNAs;Nucleic Acids Res. 20 5041–5045PubMedGoogle Scholar
  19. Bukh J and Miller R H 1994 Diagnostic and clinical implications of the different genotypes of hepatitis C virus;Hepatology 20 256–259PubMedGoogle Scholar
  20. Bukh J, Miller R H and Purcell R H 1995 Genetic heterogeneity of hepatitis C virus: quasispecies and genotypes;Semin Liver Dis. 15 41–63PubMedGoogle Scholar
  21. Carrere-Kremer S, Montpellier-Pala C, Cocquerel L, Wychowski C, Penin F and Dubuisson J 2002 Subcellular localization and topology of the p7 polypeptide of hepatitis C virus;J. Virol. 76 3720–3730PubMedGoogle Scholar
  22. Castelain S, Khorsi H, Roussel J, Francois C, Jaillon O, Capron D, Penin F, Wychowski C, Meurs E and Duverlie G 2002 Variability of the nonstructural 5A protein of hepatitis C virus type 3a isolates and relation to interferon sensitivity;J. Infect Dis. 185 573–583PubMedGoogle Scholar
  23. Cerny A and Chisari F V 1994 Immunological aspects of HCV infection;Intervirology 37 119–125PubMedGoogle Scholar
  24. Cerny A and Chisari F V 1999 Pathogenesis of chronic hepatitis C: immunological features of hepatic injury and viral persistence;Hepatology 30 595–601PubMedGoogle Scholar
  25. Cerny A, Ferrari C and Chisari F V 1994 The class I-restricted cytotoxic T lymphocyte response to predetermined epitopes in the hepatitis B and C viruses;Curr. Top. Microbiol. Immunol. 189 169–186PubMedGoogle Scholar
  26. Chang J, Yang S H, Cho Y G, Hwang S B, Hahn Y S and Sung Y C 1998 Hepatitis C virus core from two different genotypes has an oncogenic potential but is not sufficient for transforming primary rat embryo fibroblasts in cooperation with the H-ras oncogene;J. Virol. 72 3060–3065PubMedGoogle Scholar
  27. Chang K M, Thimme R, Melpolder J J, Oldach D, Pemberton J, Moorhead-Loudis J, McHutchison J G, Alter H J and Chisari F V 2001 Differential CD4(+) and CD8(+) T-cell responsiveness in hepatitis C virus infection;Hepatology 33 267–276PubMedGoogle Scholar
  28. Chen C M, You L R, Hwang L H and Lee Y H 1997 Direct interaction of hepatitis C virus core protein with the cellular lymphotoxin-beta receptor modulates the signal pathway of the lymphotoxin-beta receptor;J. Virol. 71 9417–9426PubMedGoogle Scholar
  29. Cheng J C, Chang M F and Chang S C 1999 Specific interaction between the hepatitis C virus NS5B RNA polymerase and the 3′ end of the viral RNA;J. Virol. 73 7044–7049PubMedGoogle Scholar
  30. Choo Q L, Kuo G, Weiner A J, Overby L R, Bradley D W and Houghton M 1989 Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome;Science 244 359–362PubMedGoogle Scholar
  31. Cocquerel L, Duvet S, Meunier J C, Pillez A, Cacan R, Wychowski C and Dubuisson J 1999 The transmembrane domain of hepatitis C virus glycoprotein E1 is a signal for static retention in the endoplasmic reticulum;J. Virol. 73 2641–2649PubMedGoogle Scholar
  32. Cocquerel L, Meunier J C, Pillez A, Wychowski C and Dubuisson J 1998 A retention signal necessary and sufficient for endoplasmic reticulum localization maps to the transmembrane domain of hepatitis C virus glycoprotein E2;J. Virol. 72 2183–2191PubMedGoogle Scholar
  33. Colombo M 1998 The role of hepatitis C virus in hepatocellular carcinoma;Rec. Results Cancer Res. 154 337–344Google Scholar
  34. Cotler S J, Reddy K R, McCone J, Wolfe D L, Liu A, Craft T R, Ferris M W, Conrad A J, Albrecht J, Morrissey M, Ganger D R, Rosenblate H, Blatt L M, Jensen D M and Taylor M W 2001 An analysis of acute changes in interleukin-6 levels after treatment of hepatitis C with consensus interferon;J. Interferon Cytokine Res. 21 1011–1019PubMedGoogle Scholar
  35. Crotta S, Stilla A, Wack A, D’Andrea A, Nuti S, D’Oro U, Mosca M, Filliponi F, Brunetto R M, Bonino F, Abrignani S and Valiante N M 2002 Inhibition of natural killer cells through engagement of CD81 by the major hepatitis C virus envelope protein;J. Exp. Med. 195 35–41PubMedGoogle Scholar
  36. Cucchiarini M, Kammer A R, Grabscheid B, Diepolder H M, Gerlach T J, Gruner N, Santantonio T, Reichen J, Pape G R and Cerny A 2000 Vigorous peripheral blood cytotoxic T cell response during the acute phase of hepatitis C virus infection;Cell. Immunol. 203 111–123PubMedGoogle Scholar
  37. De Francesco R, Neddermann P, Tomei L, Steinkuhler C, Gallinari P and Folgori A 2000 Biochemical and immunologic properties of the nonstructural proteins of the hepatitis C virus: implications for development of antiviral agents and vaccines;Semin Liver Dis. 20 69–83PubMedGoogle Scholar
  38. Deleersnyder V, Pillez A, Wychowski C, Blight K, Xu J, Hahn Y S, Rice C M and Dubuisson J 1997 Formation of native hepatitis C virus glycoprotein complexes;J. Virol. 71 697–704PubMedGoogle Scholar
  39. Delhem N, Sabile A, Gajardo R, Podevin P, Abadie A, Blaton M A, Kremsdorf D, Beretta L and Brechot C 2001 Activation of the interferon-inducible protein kinase PKR by hepatocellular carcinoma derived-hepatitis C virus core protein;Oncogene 20 5836–5845PubMedGoogle Scholar
  40. Enomoto N, Sakuma I, Asahina Y, Kurosaki M, Murakami T, Yamamoto C, Ogura Y, Izumi N, Marumo F and Sato C 1996 Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection;N. Engl. J. Med. 334 77–81PubMedGoogle Scholar
  41. Erickson A L, Kimura Y, Igarashi S, Eichelberger J, Houghton M, Sidney J, McKinney D, Sette A, Hughes A Land Walker C M 2001 The outcome of hepatitis C virus infection is predicted by escape mutations in epitopes targeted by cytotoxic T lymphocytes;Immunity 15 883–895PubMedGoogle Scholar
  42. Failla C, Tomei L and De Francesco R 1994 Both NS3 and NS4A are required for proteolytic processing of hepatitis C virus nonstructural proteins;J. Virol. 68 3753–3760PubMedGoogle Scholar
  43. Farci P, Bukh J and Purcell R H 1997 The quasispecies of hepatitis C virus and the host immune response;Springer Semin Immunopathol. 19 5–26PubMedGoogle Scholar
  44. Farci P, Shimoda A, Coiana A, Diaz G, Peddis G, Melpolder J C, Strazzera A, Chien D Y, Munoz S J, Balestrieri A, Purcell R H and Alter H J 2000 The outcome of acute hepatitis C predicted by the evolution of the viral quasispecies;Science 288 339–344PubMedGoogle Scholar
  45. Farci P, Shimoda A, Wong D, Cabezon T, De Gioannis D, Strazzera A, Shimizu Y, Shapiro M, Alter H J and Purcell R H 1996 Prevention of hepatitis C virus infection in chimpanzees by hyperimmune serum against the hypervariable region 1 of the envelope 2 protein;Proc. Natl. Acad. Sci. USA 93 15394–15399Google Scholar
  46. Ferri C, Monti M, La Civita L, Careccia G, Mazzaro C, Longombardo G, Lombardini F, Greco F, Pasero G, Bombardieri S et al 1994 Hepatitis C virus infection in non-Hodgkin’s B-cell lymphoma complicating mixed cryoglobulinaemia;Eur. J. Clin. Invest. 24781–784PubMedGoogle Scholar
  47. Flint M, Maidens C, Loomis-Price L D, Shotton C, Dubuisson J, Monk P, Higginbottom A, Levy S and McKeating J A 1999 Characterization of hepatitis C virus E2 glycoprotein interaction with a putative cellular receptor, CD81;J. Virol. 73 6235–6244PubMedGoogle Scholar
  48. Forns X, Purcell R H and Bukh J 1999 Quasispecies in viral persistence and pathogenesis of hepatitis C virus;Trends Microbiol. 7 402–410PubMedGoogle Scholar
  49. Fournier C, Sureau C, Coste J, Ducos J, Pageaux G, Larrey D, Domergue J and Maurel P 1998 In vitro infection of adult normal human hepatocytes in primary culture by hepatitis C virus;J. Gen. Virol. 79 2367–2374PubMedGoogle Scholar
  50. Gale M J, Korth M J, Tang N M, Tan S L, Hopkins D A, Dever T E, Polyak S J, Gretch D R and Katze M G 1997 Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein;Virology 230 217–227PubMedGoogle Scholar
  51. Gale M J, Kwieciszewski B, Dossett M, Nakao H and Katze M G 1999 Antiapoptotic and oncogenic potentials of hepatitis C virus are linked to interferon resistance by viral repression of the PKR protein kinase;J. Virol. 73 6506–6516PubMedGoogle Scholar
  52. Garcia-Retortillo M, Forns X, Feliu A, Moitinho E, Costa J, Navasa M, Rimola A and Rodes J 2002 Hepatitis C virus kinetics during and immediately after liver transplantation;Hepatology 35 680–687PubMedGoogle Scholar
  53. Gerotto M, Dal Pero F, Pontisso P, Noventa F, Gatta A and Alberti A 2000 Two PKR inhibitor HCV proteins correlate with early but not sustained response to interferon;Gastroenterology 119 1649–1655PubMedGoogle Scholar
  54. Ghosh A K, Steele R, Meyer K, Ray R and Ray R B 1999 Hepatitis C virus NS5A protein modulates cell cycle regulatory genes and promotes cell growth;J. Gen. Virol. 80 1179–1183PubMedGoogle Scholar
  55. Gontarek R R, Gutshall L L, Herold K M, Tsai J, Sathe G M, Mao J, Prescott C and Del Vecchio A M 1999 hnRNP C and polypyrimidine tract-binding protein specifically interact with the pyrimidine-rich region within the 3′NTR of the HCV RNA genome;Nucleic Acids Res. 27 1457–1463PubMedGoogle Scholar
  56. Grakoui A, McCourt D W, Wychowski C, Feinstone S M and Rice C M 1993 A second hepatitis C virus-encoded proteinase;Proc. Natl. Acad. Sci. USA 90 10583–10587PubMedGoogle Scholar
  57. Guo J T, Bichko V V and Seeger C 2001 Effect of alpha interferon on the hepatitis C virus replicon;J. Virol. 75 8516–8523PubMedGoogle Scholar
  58. Hahn C S, Cho Y G, Kang B S, Lester I M and Hahn Y S 2000 The HCV core protein acts as a positive regulator of fasmediated apoptosis in a human lymphoblastoid T cell line;Virology 276 127–137PubMedGoogle Scholar
  59. He X S, Rehermann B, Lopez-Labrador F X, Boisvert J, Cheung R, Mumm J, Wedemeyer H, Berenguer M, Wright T L, Davis M M and Greenberg H B 1999 Quantitative analysis of hepatitis C virus-specific CD8(+) T cells in peripheral blood and liver using peptide-MHC tetramers;Proc. Natl. Acad. Sci. USA 96 5692–5697PubMedGoogle Scholar
  60. Hijikata M, Mizushima H, Akagi T, Mori S, Kakiuchi N, Kato N, Tanaka T, Kimura K and Shimotohno K 1993 Two distinct proteinase activities required for the processing of a putative nonstructural precursor protein of hepatitis C virus;J. Virol. 67 4665–4675PubMedGoogle Scholar
  61. Hugle T, Fehrmann F, Bieck E, Kohara M, Krausslich H G, Rice C M, Blum H E and Moradpour D 2001 The hepatitis C virus nonstructural protein 4B is an integral endoplasmic reticulum membrane protein;Virology 284 70–81PubMedGoogle Scholar
  62. Hussy P, Langen H, Mous J and Jacobsen H 1996 Hepatitis C virus core protein: carboxy-terminal boundaries of two processed species suggest cleavage by a signal peptide peptidase;Virology 224 93–104PubMedGoogle Scholar
  63. Ishii K, Rosa D, Watanabe Y, Katayama T, Harada H, Wyatt C, Kiyosawa K, Aizaki H, Matsuura Y, Houghton M, Abrignani S and Miyamura T 1998 High titers of antibodies inhibiting the binding of envelope to human cells correlate with natural resolution of chronic hepatitis C;Hepatology 28 1117–1120PubMedGoogle Scholar
  64. Kakumu S, Ito S, Ishikawa T, Mita Y, Tagaya T, Fukuzawa Y and Yoshioka K 2000 Decreased function of peripheral blood dendritic cells in patients with hepatocellular carcinoma with hepatitis B and C virus infection;J. Gastroenterol. Hepatol. 15 431–436PubMedGoogle Scholar
  65. Kanto T, Hayashi N, Takehara T, Tatsumi T, Kuzushita N, Ito A, Sasaki Y, Kasahara A and Hori M 1999 Impaired allostimulatory capacity of peripheral blood dendritic cells recovered from hepatitis C virus-infected individuals;J. Immunol. 162 5584–5591PubMedGoogle Scholar
  66. Kato N, Ootsuyama Y, Ohkoshi S, Nakazawa T, Sekiya H, Hijikata M and Shimotohno K 1992 Characterization of hypervariable regions in the putative envelope protein of hepatitis C virus;Biochem. Biophys. Res. Commun. 189 119–127PubMedGoogle Scholar
  67. Kato N, Sekiya H, Ootsuyama Y, Nakazawa T, Hijikata M, Ohkoshi S and Shimotohno K 1993 Humoral immune response to hypervariable region 1 of the putative envelope glycoprotein (gp70) of hepatitis C virus;J. Virol. 67 3923–3930PubMedGoogle Scholar
  68. Kato N, Yoshida H, Ono-Nita S K, Kato J, Goto T, Otsuka M, Lan K G, Matsushima K, Shiratori Y and Omata M 2000 Activation of intracellular signalling by hepatitis B and C viruses; C-viral core is the most potent signal inducer;Hepatology 32 405–412PubMedGoogle Scholar
  69. Kim J L, Morgenstern K A, Lin C, Fox T, Dwyer M D, Landro J A, Chambers S P, Markland W, Lepre C A, O’Malley E T, Harbeson S L, Rice C M, Murcko M A, Caron P R and Thomson J A 1996 Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide;Cell 87 343–355PubMedGoogle Scholar
  70. Kimball P, Elswick R K and Shiffman M 2001 Ethnicity and cytokine production gauge response of patients with hepatitis C to interferon-alpha therapy;J. Med. Virol. 65 510–516PubMedGoogle Scholar
  71. Kitay-Cohen Y, Amiel A, Hilzenrat N, Buskila D and Lishner M 1999 Bcl-2 rearrangement in patients with chronic hepatitis C associated with essential mixed cryoglobulinemia type II;Hepatology (Suppl.) 30 238AGoogle Scholar
  72. Koch J O and Bartenschlager R 1999 Modulation of hepatitis C virus NS5A hyperphosphorylation by nonstructural proteins NS3, NS4A and NS4B;J. Virol. 73 7138–7146PubMedGoogle Scholar
  73. Kolykhalov A A, Feinstone S M and Rice CM 1996 Identification of a highly conserved sequence element at the 3’ terminus of hepatitis C virus genome RNA;J. Virol. 70 3363–3371PubMedGoogle Scholar
  74. Kruger M, Beger C, Li Q X, Welch P J, Tritz R, Leavitt M, Barber J R and Wong-Staal F 2000 Identification of eIF2B-gamma and eIF2gamma as cofactors of hepatitis C virus internal ribosome entry site-mediated translation using a functional genomics approach;Proc. Natl. Acad. Sci. USA 97 8566–8571PubMedGoogle Scholar
  75. Kumar U, Monjardino J and Thomas H C 1994 Hypervariable region of hepatitis C virus envelope glycoprotein (E2/NS1) in an agammaglobulinemic patient;Gastroenterology 106 1072–1075PubMedGoogle Scholar
  76. Lai M M and Ware C F 2000 Hepatitis C virus core protein: possible roles in viral pathogenesis;Curr. Top. Microbiol. Immunol. 242 117–134PubMedGoogle Scholar
  77. Lai M M C 2000 Hepatitis C Virus Proteins: Direct Link to Hepatic Oxidative Stress, Steatosis, Carcinogenesis and More;Gastroenterology 122 568–570Google Scholar
  78. Lanford R E, Bigger C, Bassett S and Klimpel G 2001 The chimpanzee model of hepatitis C virus infections;Ilar J. 42 117–126PubMedGoogle Scholar
  79. Large M K, Kittlesen D J and Hahn Y S 1999 Suppression of host immune response by the core protein of hepatitis C virus: possible implications for hepatitis C virus persistence;J. Immunol. 162 931–938PubMedGoogle Scholar
  80. Laskus T, Radkowski M, Wilkinson J, Vargas H and Rakela J 2002 The origin of hepatitis C virus reinfecting transplanted livers: serum-derived versus peripheral blood mononuclear cell-derived virus;J. Infect. Dis. 185 417–421PubMedGoogle Scholar
  81. Lechner F, Wong D K, Dunbar P R, Chapman R, Chung R T, Dohrenwend P, Robbins G, Phillips R, Klenerman P and Walker B D 2000 Analysis of successful immune responses in persons infected with hepatitis C virus;J. Exp. Med. 191 1499–1512PubMedGoogle Scholar
  82. Lerat H, Berby F, Trabaud M A, Vidalin O, Major M, Trepo C and Inchauspe G 1996 Specific detection of hepatitis C virus minus strand RNA in hematopoietic cells;J. Clin. Invest. 97 845–851PubMedGoogle Scholar
  83. Liang T J, Rehermann B, Seeff L B and Hoofnagle J H 2000 Pathogenesis, natural history, treatment and prevention of hepatitis C;Ann. Internal Med. 132 296–305Google Scholar
  84. Liberman E, Fong Y L, Selby M J, Choo Q L, Cousens L, Houghton M and Yen T S 1999 Activation of the grp78 and grp94 promoters by hepatitis C virus E2 envelope protein;J. Virol. 73 3718–3722PubMedGoogle Scholar
  85. Liu Q, Tackney C, Bhat R A, Prince A M and Zhang P 1997 Regulated processing of hepatitis C virus core protein is linked to subcellular localization;J. Virol. 71 657–662PubMedGoogle Scholar
  86. Liu Z X, Nishida H, He J W, Lai M M, Feng N and Dennert G 2002 Hepatitis C virus genotype 1b core protein does not exert immunomodulatory effects on virus-induced cellular immunity;J. Virol. 76 990–997PubMedGoogle Scholar
  87. Lo S and Lin H H 2001 Variations within hepatitis C virus E2 protein and response to interferon treatment;Virus Res. 75 107–112PubMedGoogle Scholar
  88. Lo S Y, Selby M, Tong M and Ou J H 1994 Comparative studies of the core gene products of two different hepatitis C virus isolates: two alternative forms determined by a single amino acid substitution;Virology 199 124–131PubMedGoogle Scholar
  89. Lohmann, V, Korner F, Dobierzewska A and Bartenschlager R 2001 Mutations in hepatitis C virus RNAs conferring cell culture adaptation;J. Virol. 75 1437–1449PubMedGoogle Scholar
  90. Lohmann V, Korner F, Koch J, Herian U, Theilmann L and Bartenschlager R 1999 Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line;Science 285 110–113PubMedGoogle Scholar
  91. Luo G 1999 Cellular proteins bind to the polyU tract of the 3′ untranslated region of hepatitis C virus RNA genome;Virology 256 105–118PubMedGoogle Scholar
  92. Major M E and Feinstone S M 1997 The molecular virology of hepatitis C;Hepatology 25 1527–1538PubMedGoogle Scholar
  93. Marusawa H, Hijikata M, Chiba T and Shimotohno K 1999 Hepatitis C virus core protein inhibits Fas- and tumor necrosis factor alpha-mediated apoptosis via NF-kappaB activation;J. Virol. 73 4713–4720PubMedGoogle Scholar
  94. Matsumoto M, Hsieh T Y, Zhu N, VanArsdale T, Hwang S B, Jeng K S, Gorbalenya A E, Lo S Y, Ou J H, Ware C F and Lai M M 1997 Hepatitis C virus core protein interacts with the cytoplasmic tail of lymphotoxin-beta receptor;J. Virol. 71 1301–1309PubMedGoogle Scholar
  95. McHutchison J G, Gordon S C, Schiff E R, Shiffman M L, Lee W M, Rustgi V K, Goodman Z D, Ling M H, Cort S and Albrecht J K 1998 Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C Hepatitis Interventional Therapy Group [see comments];N. Engl. J. Med. 339 1485–1492PubMedGoogle Scholar
  96. Mercer D F, Schiller D E, Elliott J F, Douglas D N, Hao C, Rinfret A, Addison W R, Fischer K P, Churchill T A, Lakey J R, Tyrrell D L and Kneteman N M 2001 Hepatitis C virus replication in mice with chimeric human livers;Nat. Med. 7 927–933PubMedGoogle Scholar
  97. Mizutani T, Kato N, Saito S, Ikeda M, Sugiyama K and Shimotohno K 1996 Characterization of hepatitis C virus replication in cloned cells obtained from a human T-cell leukemia virus type 1-infected cell line, MT-2;J. Virol. 70 7219–7223PubMedGoogle Scholar
  98. Monteverde A, Ballare M and Pileri S 1997 Hepatic lymphoid aggregates in chronic hepatitis C and mixed cryoglobulinemia;Springer Semin Immunopathol. 19 99–110PubMedGoogle Scholar
  99. Naganuma A, Nozaki A, Tanaka T, Sugiyama K, Takagi H, Mori M, Shimotohno K and Kato N 2000 Activation of the Interferon-Inducible 2′-5′-oligoadenylate synthetase gene by hepatitis C virus core protein;J. Virol. 74 8744–8750PubMedGoogle Scholar
  100. Nakajima N, Hijikata M, Yoshikura H and Shimizu Y K 1996 Characterization of long-term cultures of hepatitis C virus;J. Virol. 70 3325–3329PubMedGoogle Scholar
  101. Napoli J, Bishop G A, McGuinness P H, Painter D M and McCaughan G W 1996 Progressive liver injury in chronic hepatitis C infection correlates with increased intrahepatic expression of Th1-associated cytokines;Hepatology 24 759–765PubMedGoogle Scholar
  102. Neuman M G, Benhamou J P, Malkiewicz I M, Akremi R, Shear N H, Asselah T, Ibrahim A, Boyer N, Martinot-Peignoux M, Jacobson-Brown P, Katz G G, Le Breton V, Le Guludec G, Suneja A and Marcellin P 2001 Cytokines as predictors for sustained response and as markers for immunomodulation in patients with chronic hepatitis C;Clin. Biochem. 34 173–182PubMedGoogle Scholar
  103. Ogata N, Alter H J, Miller R H and Purcell R H 1991 Nucleotide sequence and mutation rate of the H strain of hepatitis C virus;Proc. Natl. Acad. Sci. USA 88 3392–3396PubMedGoogle Scholar
  104. Oh J W, Ito T and Lai M M 1999 A recombinant hepatitis C virus RNA-dependent RNA polymerase capable of copying the full-length viral RNA;J. Virol. 73 7694–7702PubMedGoogle Scholar
  105. Oh J W, Sheu G T and Lai M M 2000 Template requirement and initiation site selection by hepatitis C virus polymerase on a minimal viral RNA template;J. Biol. Chem. 275 17710–17717PubMedGoogle Scholar
  106. Park J S, Yang J M and Min M K 2000 Hepatitis C virus non-structural protein NS4B transforms NIH3T3 cells in cooperation with the Ha-ras oncogene;Biochem. Biophys. Res. Commun. 267 581–587PubMedGoogle Scholar
  107. Paul W E 1999Fundamental immunology 4th edition (Philadelphia: Lippincott-Raven)Google Scholar
  108. Pavio N, Taylor D R and Lai M M 2002 Detection of a novel unglycosylated form of hepatitis C virus E2 envelope protein that is located in the cytosol and interacts with PKR;J. Virol. 76 1265–1272PubMedGoogle Scholar
  109. Pestova T V, Shatsky I N, Fletcher S P, Jackson R J and Hellen C U 1998 A prokaryotic-like mode of cytoplasmic eukaryotic ribosome binding to the initiation codon during internal translation initiation of hepatitis C and classical swine fever virus RNAs;Genes Dev. 12 67–83PubMedGoogle Scholar
  110. Pietschmann T, Lohmann V, Kaul A, Krieger N, Rinck G, Rutter G, Strand D and Bartenschlager R 2002 Persistent and transient replication of full-length hepatitis C virus genomes in cell culture;J. Virol. 76 4008–4021PubMedGoogle Scholar
  111. Pileri P, Uematsu Y, Campagnoli S, Galli G, Falugi F, Petracca R, Weiner A J, Houghton M, Rosa D, Grandi G and Abrignani S 1998 Binding of hepatitis C virus to CD81;Science 282 938–941PubMedGoogle Scholar
  112. Pioltelli P, Zehender G, Monti G, Monteverde A and Galli M 1996 HCV and non-Hodgkin lymphoma;Lancet 347 624–625PubMedGoogle Scholar
  113. Podevin P, Sabile A, Gajardo R, Delhem N, Abadie A, Lozach P Y, Beretta L and Brechot C 2001 Expression of hepatitis C virus NS5A natural mutants in a hepatocytic cell line inhibits the antiviral effect of interferon in a PKR-independent manner;Hepatology 33 1503–1511PubMedGoogle Scholar
  114. Polyak S J, Khabar K S, Paschal D M, Ezelle H J, Duverlie G, Barber G N, Levy D E, Mukaida N and Gretch D R 2001a Hepatitis C virus nonstructural 5A protein induces interleukin-8, leading to partial inhibition of the interferon-induced antiviral response;J. Virol. 75 6095–6106PubMedGoogle Scholar
  115. Polyak S J, Khabar K S, Rezeiq M and Gretch D R 2001b Elevated levels of interleukin-8 in serum are associated with hepatitis C virus infection and resistance to interferon therapy;J. Virol. 75 6209–6211PubMedGoogle Scholar
  116. Poynard T, Marcellin P, Lee S S, Niederau C, Minuk G S, Ideo G, Bain V, Heathcote J, Zeuzem S, Trepo C and Albrecht J 1998 Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus International Hepatitis Interventional Therapy Group (IHIT);Lancet 352 1426–1432PubMedGoogle Scholar
  117. Pozzato G, Mazzaro C, Crovatto M, Modolo M L, Ceselli S, Mazzi G, Sulfaro S, Franzin F, Tulissi P and Moretti M 1994 Low-grade malignant lymphoma, hepatitis C virus infection and mixed cryoglobulinemia;Blood 84 3047–3053PubMedGoogle Scholar
  118. Puig-Basagoiti F, Saiz J C, Forns X, Ampurdanes S, Gimenez-Barcons M, Franco S, Sanchez-Fueyo A, Costa J, Sanchez-Tapias J M and Rodes J 2001 Influence of the genetic heterogeneity of the ISDR and PePHD regions of hepatitis C virus on the response to interferon therapy in chronic hepatitis C;J. Med. Virol. 65 35–44PubMedGoogle Scholar
  119. Quinn E R, Chan C H, Hadlock K G, Foung S K, Flint M and Levy S 2001 The B-cell receptor of a hepatitis C virus (HCV)-associated non-Hodgkin lymphoma binds the viral E2 envelope protein, implicating HCV in lymphomagenesis;Blood 98 3745–3749PubMedGoogle Scholar
  120. Ray R B, Lagging L M, Meyer K, Steele R and Ray R 1995 Transcriptional regulation of cellular and viral promoters by the hepatitis C virus core protein;Virus Res. 37 209–220PubMedGoogle Scholar
  121. Ray R B, Lagging L M, Meyer K and Ray R 1996 Hepatitis C virus core protein cooperates with ras and transforms primary rat embryo fibroblasts to tumorigenic phenotype;J. Virol. 70 4438–4443PubMedGoogle Scholar
  122. Ray R B, Steele R, Meyer K and Ray R 1997 Transcriptional repression of p53 promoter by hepatitis C virus core protein;J. Biol. Chem. 272 10983–10986PubMedGoogle Scholar
  123. Ray R B, Steele R, Meyer K and Ray R 1998 Hepatitis C virus core protein represses p21WAF1/Cip1/Sid1 promoter activity;Gene 208 331–336PubMedGoogle Scholar
  124. Rosa D, Campagnoli S, Moretto C, Guenzi E, Cousens L, Chin M, Dong C, Weiner A J, Lau J Y, Choo Q L, Chien D, Pileri P, Houghton M and Abrignani S 1996 A quantitative test to estimate neutralizing antibodies to the hepatitis C virus: cytofluorimetric assessment of envelope glycoprotein 2 binding to target cells;Proc. Natl. Acad. Sci. USA 93 1759–1763PubMedGoogle Scholar
  125. Ruggieri A, Harada T, Matsuura Y and Miyamura T 1997 Sensitization to Fas-mediated apoptosis by hepatitis C virus core protein;Virology 229 68–76PubMedGoogle Scholar
  126. Sakamuro D, Furukawa T and Takegami T 1995 Hepatitis C virus nonstructural protein NS3 transforms NIH 3T3 cells;J. Virol. 69 3893–3896PubMedGoogle Scholar
  127. Santolini E, Migliaccio G and La Monica N 1994 Biosynthesis and biochemical properties of the hepatitis C virus core protein;J. Virol. 68 3631–3641PubMedGoogle Scholar
  128. Sarih M, Bouchrit N and Benslimane A 2000 Different cytokine profiles of peripheral blood mononuclear cells from patients with persistent and self-limited hepatitis C virus infection;Immunol. Lett. 74 117–120PubMedGoogle Scholar
  129. Schiappa D A, Mittal C, Brown J A and Mika B P 2002 Relationship of Hepatitis C Genotype 1 NS5A Sequence Mutations to Early Phase Viral Kinetics and Interferon Effectiveness;J. Infect. Dis. 185 868–877PubMedGoogle Scholar
  130. Schmidt-Mende J, Bieck E, Hugle T, Penin F, Rice C M, Blum H E and Moradpour D 2001 Determinants for membrane association of the hepatitis C virus RNA-dependent RNA polymerase;J. Biol. Chem. 276 44052–44063PubMedGoogle Scholar
  131. Shapiro S, Gershtein V, Elias N, Zuckerman E, Salman N and Lahat N 1998 mRNA cytokine profile in peripheral blood cells from chronic hepatitis C virus (HCV)-infected patients: effects of interferon-alpha (IFN-alpha) treatment;Clin. Exp. Immunol. 114 55–6PubMedGoogle Scholar
  132. Shi S T and Lai M M 2001 Hepatitis C viral RNA: challenges and promises;Cell. Mol. Life Sci. 58 1276–1295PubMedGoogle Scholar
  133. Shi S T, Polyak S J, Tu H, Taylor D R, Gretch D Rand Lai M M C 2002 Hepatitis C virus NS5A colocalizes with the core protein on lipid droplets and interacts with apolipoproteins;Virology 292 198–210PubMedGoogle Scholar
  134. Simmonds P 1994 Variability of hepatitis C virus genome;Curr. Stud. Hematol. Blood Transfusion 61 12–35Google Scholar
  135. Simmonds P, Holmes E C, Cha T A, Chan S W, McOmish F, Irvine B, Beall E, Yap P L, Kolberg J and Urdea M S 1993 Classification of hepatitis C virus into six major genotypes and a series of subtypes by phylogenetic analysis of the NS-5 region;J. Gen. Virol. 74 2391–2399PubMedGoogle Scholar
  136. Simmonds P, Smith D B, McOmish F, Yap P L, Kolberg J, Urdea M S and Holmes E C 1994 Identification of genotypes of hepatitis C virus by sequence comparisons in the core, E1 and NS-5 regions;J. Gen. Virol. 75 1053–1061PubMedGoogle Scholar
  137. Sizova D V, Kolupaeva V G, Pestova T V, Shatsky I N and Hellen C U 1998 Specific interaction of eukaryotic translation initiation factor 3 with the 5′ nontranslated regions of hepatitis C virus and classical swine fever virus RNAs;J. Virol. 72 4775–4782PubMedGoogle Scholar
  138. Sun J, Bodola F, Fan X, Irshad H, Soong L, Lemon S M and Chan T-H 2001 Hepatitis C virus core and envelope proteins do not suppress the host’s ability to clear a hepatic viral infection;J. Virol. 75 11992–11998PubMedGoogle Scholar
  139. Sung V M-H, Shimodaira S, Doughty A L, Picchio G R, Can H, Yen T-S B, Lindsay K L, Levine A M and Lai M M C 2003 Establishment of B-cell lymphoma cell lines persistently infected with hepatitis C virusin vivo andin vitro: The apoptotic effects of virus infection;J. Virol. 77 2134–2146PubMedGoogle Scholar
  140. Suzuki R, Matsuura Y, Suzuki T, Ando A, Chiba J, Harada S, Saito I and Miyamura T 1995 Nuclear localization of the truncated hepatitis C virus core protein with its hydrophobic C terminus deleted;J. Gen. Virol. 76 53–61PubMedGoogle Scholar
  141. Tai C L, Chi W K, Chen D S and Hwang L H 1996 The helicase activity associated with hepatitis C virus nonstructural protein 3 (NS3);J. Virol. 70 8477–8484PubMedGoogle Scholar
  142. Tan S L, Nakao H, He Y, Vijaysri S, Neddermann P, Jacobs B L, Mayer B J and Katze M G1999 NS5A, a nonstructural protein of hepatitis C virus, binds growth factor receptorbound protein 2 adaptor protein in a Src homology 3 domain/ ligand-dependent manner and perturbs mitogenic signaling;Proc. Natl. Acad. Sci. USA 96 5533–5538PubMedGoogle Scholar
  143. Taylor D R, Shi S T, Romano P R, Barber G N and Lai M M 1999 Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein;Science 285 107–110PubMedGoogle Scholar
  144. Tsai S L, Chen Y M, Chen M H, Huang C Y, Sheen I S, Yeh C T, Huang J H, Kuo G C and Liaw Y F 1998 Hepatitis C virus variants circumventing cytotoxic T lymphocyte activity as a mechanism of chronicity;Gastroenterology 115 954–965PubMedGoogle Scholar
  145. Tseng C T and Klimpel G R 2002 Binding of the hepatitis C virus envelope protein E2 to CD81 inhibits natural killer cell functions;J. Exp. Med. 195 43–49PubMedGoogle Scholar
  146. Tu H, Gao L, Shi S T, Taylor D R, Yang T, Mircheff A K, Wen Y, Gorbalenya A E, Hwang S B and Lai M M C 1999 Hepatitis C virus RNA polymerase and NS5A complex with a SNARE-like protein;Virology 263 30–41PubMedGoogle Scholar
  147. Valiante N M, D’Andrea A, Crotta S, Lechner F, Klenerman P, Nuti S, Wack A and Abrignani S 2000 Life, activation and death of intrahepatic lymphocytes in chronic hepatitis C;Immunol. Rev. 174 77–89PubMedGoogle Scholar
  148. Wack A, Soldaini E, Tseng C, Nuti S, Klimpel G and Abrignani S 2001 Binding of the hepatitis C virus envelope protein E2 to CD81 provides a co-stimulatory signal for human T cells;Eur. J. Immunol. 31 166–175PubMedGoogle Scholar
  149. Watashi K, Hijikata M, Marusawa H, Doi T and Shimotohno K 2001 Cytoplasmic localization is important for transcription factor nuclear factor-kappa B activation by hepatitis C virus core protein through its amino terminal region;Virology 286 391–402PubMedGoogle Scholar
  150. Weiner A, Erickson A L, Kansopon J, Crawford K, Muchmore E, Hughes A L, Houghton M and Walker C M 1995 Persistent hepatitis C virus infection in a chimpanzee is associated with emergence of a cytotoxic T lymphocyte escape variant;Proc. Natl. Acad. Sci. USA 92 2755–2759PubMedGoogle Scholar
  151. Weiner A J, Brauer M J, Rosenblatt J, Richman K H, Tung J, Crawford K, Bonino F, Saracco G, Choo Q L, Houghton M et al 1991 Variable and hypervariable domains are found in the regions of HCV corresponding to the flavivirus envelope and NS1 proteins and the pestivirus envelope glycoproteins;Virology 180 842–858PubMedGoogle Scholar
  152. Weiner A J, Geysen H M, Christopherson C, Hall J E, Mason T J, Saracco G, Bonino F, Crawford K, Marion C D, Crawford K Aet al 1992 Evidence for immune selection of hepatitis C virus (HCV) putative envelope glycoprotein variants: potential role in chronic HCV infections;Proc. Natl. Acad. Sci. USA 89 3468–3472PubMedGoogle Scholar
  153. Yamashita T, Kaneko S, Shirota T, Qin W, Nomura T, Kobayashi K and Murakami S 1998 RNA-dependent RNA polymerase activity of the soluble recombinant hepatitis C virus NS5B protein truncated at the C-terminal region;J. Biol. Chem. 273 15479–15486PubMedGoogle Scholar
  154. Yanagi M, Purcell R H, Emerson S U and Bukh J 1997 Transcripts from a single full-length cDNA clone of hepatitis C virus are infectious when directly transfected into the liver of a chimpanzee;Proc. Natl. Acad. Sci. USA 94 8738–8743PubMedGoogle Scholar
  155. Yanagi M, Purcell R H, Emerson S U and Bukh J 1999a Hepatitis C virus: an infectious molecular clone of a second major genotype 2a and lack of viability of intertypic 1a and 2a chimeras;Virology 262 250–263PubMedGoogle Scholar
  156. Yanagi M, St Claire M, Emerson S U, Purcell R H and Bukh J 1999b In vivo analysis of the 3′ untranslated region of the hepatitis C virus after in vitro mutagenesis of an infectious cDNA clone;Proc. Natl. Acad. Sci. USA 96 2291–2295Google Scholar
  157. Yanagi M, St Claire M, Shapiro M, Emerson S U, Purcell R H and Bukh J 1998 Transcripts of a chimeric cDNA clone of hepatitis C virus genotype 1b are infectious in vivo;Virology 244 161–172PubMedGoogle Scholar
  158. Yao Z Q, Nguyen D T, Hiotellis A I and Hahn Y S 2001 Hepatitis C virus core protein inhibits human T lymphocyte responses by a complement-dependent regulatory pathway;J. Immunol. 167 5264–5272PubMedGoogle Scholar
  159. Zhu N, Khoshnan A, Schneider R, Matsumoto M, Dennert G, Ware C and Lai M M 1998 Hepatitis C virus core protein binds to the cytoplasmic domain of tumor necrosis factor (TNF) receptor 1 and enhances TNF-induced apoptosis;J. Virol. 72 3691–3697PubMedGoogle Scholar
  160. Zhu N, Ware C F and Lai M M 2001 Hepatitis C virus core protein enhances FADD-mediated apoptosis and suppresses TRADD signaling of tumor necrosis factor receptor;Virology 283 178–187PubMedGoogle Scholar
  161. Zignego A L, Giannelli F, Marrocchi M E, Mazzocca A, Ferri C, Giannini C, Monti M, Caini P, Villa G L, Laffi G and Gentilini P 2000 T(14;18) translocation in chronic hepatitis C virus infection;Hepatology 31 474–479PubMedGoogle Scholar
  162. Zuckerman E, Zuckerman T, Levine A M, Douer D, Gutekunst K, Mizokami M, Qian D G, Velankar M, Nathwani B N and Fong T L 1997 Hepatitis C virus infection in patients with B-cell non-Hodgkin lymphoma;Ann. Int. Med. 127 423–428PubMedGoogle Scholar
  163. Zuckerman E, Zuckerman T, Sahar D, Streichman S, Attias D, Sabo E, Yeshurun D and Rowe J 2001 bcl-2 and immunoglobulin gene rearrangement in patients with hepatitis C virus infection;Br. J. Haematol. 112 364–369PubMedGoogle Scholar

Copyright information

© Indian Academy of Sciences 2003

Authors and Affiliations

  • Nicole Pavio
    • 1
  • Michael M. C. Lai
    • 1
    • 2
  1. 1.Department of Molecular Microbiology and ImmunologyUniversity of Southern California,Keck School of MedicineLos AngelesUSA
  2. 2.Howard Hughes Medical InstituteUniversity of Southern CaliforniaKeck School of MedicineLos AngelesUSA

Personalised recommendations