Adaptive Immune Responses in Hepatitis C Virus Infection

  • Christoph Neumann-Haefelin
  • Robert Thimme
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 369)


The adaptive immune response plays a central role in the outcome of hepatitis C virus (HCV) infection. Indeed, spontaneous viral clearance is associated with an early neutralizing antibody response as well as vigorous and sustained HCV-specific CD4+ and CD8+ T cell responses. In persistent HCV infection, however, all three components of the antiviral adaptive immune response fail due to different viral evasion strategies. In this chapter, we will describe the components of a successful immune response against HCV and summarize the mechanisms of immune failure. We will also highlight characteristics of protective CD8+ T cell responses which is the key factor to the design of an efficacious vaccine.


Cell Epitope Viral Clearance Neutralize Antibody Response Viral Escape Viral Quasispecies 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Abel M, Sene D, Pol S et al (2006) Intrahepatic virus-specific IL-10-producing CD8 T cells prevent liver damage during chronic hepatitis C virus infection. Hepatology 44:1607–1616PubMedGoogle Scholar
  2. Accapezzato D, Francavilla V, Paroli M et al (2004) Hepatic expansion of a virus-specific regulatory CD8 (+) T cell population in chronic hepatitis C virus infection. J Clin Invest 113:963–972PubMedGoogle Scholar
  3. Adams G, Kuntz S, Rabalais G, Bratcher D, Tamburro CH, Kotwal GJ (1997) Natural recovery from acute hepatitis C virus infection by agammaglobulinemic twin children. Pediatr Infect Dis J 16:533–534PubMedGoogle Scholar
  4. Alatrakchi N, Koziel M (2009) Regulatory T cells and viral liver disease. J Viral Hepat 16:223–229PubMedGoogle Scholar
  5. Alatrakchi N, Graham CS, van der Vliet HJ, Sherman KE, Exley MA, Koziel MJ (2007) Hepatitis C virus (HCV)-specific CD8+ cells produce transforming growth factor beta that can suppress HCV-specific T-cell responses. J Virol 81:5882–5892PubMedGoogle Scholar
  6. Barber DL, Wherry EJ, Masopust D et al (2006) Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439:682–687PubMedGoogle Scholar
  7. Barnes E, Folgori A, Capone S et al (2012) Novel adenovirus-based vaccines induce broad and sustained T cell responses to HCV in man. Sci Transl Med 4(115):115ra111Google Scholar
  8. Bartosch B, Bukh J, Meunier JC et al (2003) In vitro assay for neutralizing antibody to hepatitis C virus: evidence for broadly conserved neutralization epitopes. Proc Natl Acad Sci USA 100:14199–14204PubMedGoogle Scholar
  9. Bengsch B, Seigel B, Ruhl M et al (2010) Coexpression of PD-1, 2B4, CD160 and KLRG1 on exhausted HCV-specific CD8+ T cells is linked to antigen recognition and T cell differentiation. PLoS Pathog 6:e1000947PubMedGoogle Scholar
  10. Bengsch B, Spangenberg HC, Kersting N et al (2007) 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 81:945–953PubMedGoogle Scholar
  11. Billerbeck E, Thimme R (2007) Parallel expansion of human virus-specific FoxP3- effector memory and de novo generated FoxP3+ regulatory CD8+ T cells upon antigen recognition in vitro. J Immunol 179:1039–1048PubMedGoogle Scholar
  12. Billerbeck E, Thimme R (2008) CD8+ regulatory T cells in persistent human viral infections. Hum Immunol 69:771–775PubMedGoogle Scholar
  13. Billerbeck E, Kang YH, Walker L et al (2010) Analysis of CD161 expression on human CD8+ T cells defines a distinct functional subset with tissue-homing properties. Proc Natl Acad Sci USA 107:3006–3011PubMedGoogle Scholar
  14. Blackburn SD, Shin H, Haining WN et al (2009) Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 10:29–37PubMedGoogle Scholar
  15. Boettler T, Spangenberg HC, Neumann-Haefelin C et al (2005) 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 79:7860–7867PubMedGoogle Scholar
  16. Bolacchi F, Sinistro A, Ciaprini C et al (2006) Increased hepatitis C virus (HCV)-specific CD4+ CD25+ regulatory T lymphocytes and reduced HCV-specific CD4+ T cell response in HCV-infected patients with normal versus abnormal alanine aminotransferase levels. Clin Exp Immunol 144:188–196PubMedGoogle Scholar
  17. Bowen DG, Walker CM (2005) Mutational escape from CD8+ T cell immunity: HCV evolution, from chimpanzees to man. J Exp Med 201:1709–1714PubMedGoogle Scholar
  18. Brimacombe CL, Grove J, Meredith LW et al (2011) Neutralizing antibody-resistant hepatitis C virus cell-to-cell transmission. J Virol 85:596–605PubMedGoogle Scholar
  19. Bull RA, Luciani F, McElroy K et al (2011) Sequential bottlenecks drive viral evolution in early acute hepatitis C virus infection. PLoS Pathog 7:e1002243PubMedGoogle Scholar
  20. Cabrera R, Tu Z, Xu Y, Firpi RJ, Rosen HR, Liu C, Nelson DR (2004) An immunomodulatory role for CD4(+)CD25(+) regulatory T lymphocytes in hepatitis C virus infection. Hepatology 40:1062–1071PubMedGoogle Scholar
  21. Chang KM, Rehermann B, McHutchison JG, Pasquinelli C, Southwood S, Sette A, Chisari FV (1997) Immunological significance of cytotoxic T lymphocyte epitope variants in patients chronically infected by the hepatitis C virus. J Clin Invest 100:2376–2385PubMedGoogle Scholar
  22. Claassen MA, de Knegt RJ, Tilanus HW, Janssen HL, Boonstra A (2010) Abundant numbers of regulatory T cells localize to the liver of chronic hepatitis C infected patients and limit the extent of fibrosis. J Hepatol 52:315–321PubMedGoogle Scholar
  23. Cooper S, Erickson AL, Adams EJ et al (1999) Analysis of a successful immune response against hepatitis C virus. Immunity 10:439–449PubMedGoogle Scholar
  24. Cox AL, Mosbruger T, Lauer GM, Pardoll D, Thomas DL, Ray SC (2005a) Comprehensive analyses of CD8+ T cell responses during longitudinal study of acute human hepatitis C. Hepatology 42:104–112PubMedGoogle Scholar
  25. Cox AL, Mosbruger T, Mao Q et al (2005b) Cellular immune selection with hepatitis C virus persistence in humans. J Exp Med 201:1741–1752PubMedGoogle Scholar
  26. Cusick MF, Schiller JJ, Gill JC, Eckels DD (2011) Hepatitis C virus induces regulatory T cells by naturally occurring viral variants to suppress T cell responses. Clin Dev Immunol 2011:806061PubMedGoogle Scholar
  27. Day CL, Lauer GM, Robbins GK et al (2002) Broad specificity of virus-specific CD4+ T-helper-cell responses in resolved hepatitis C virus infection. J Virol 76:12584–12595PubMedGoogle Scholar
  28. Day CL, Seth NP, Lucas M et al (2003) Ex vivo analysis of human memory CD4 T cells specific for hepatitis C virus using MHC class II tetramers. J Clin Invest 112:831–842PubMedGoogle Scholar
  29. Day CL, Kaufmann DE, Kiepiela P et al (2006) PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443:350–354PubMedGoogle Scholar
  30. Dazert E, Neumann-Haefelin C, Bressanelli S et al (2009) Loss of viral fitness and cross-recognition by CD8+ T cells limit HCV escape from a protective HLA-B27-restricted human immune response. J Clin Invest 119:376–386PubMedGoogle Scholar
  31. Di Lorenzo C, Angus AG, Patel AH (2011) Hepatitis C virus evasion mechanisms from neutralizing antibodies. Viruses 3:2280–2300PubMedGoogle Scholar
  32. Diepolder HM, Zachoval R, Hoffmann RM et al (1995) Possible mechanism involving T-lymphocyte response to non-structural protein 3 in viral clearance in acute hepatitis C virus infection. Lancet 346:1006–1007PubMedGoogle Scholar
  33. Diepolder HM, Gerlach JT, Zachoval R et al (1997) Immunodominant CD4+ T-cell epitope within nonstructural protein 3 in acute hepatitis C virus infection. J Virol 71:6011–6019PubMedGoogle Scholar
  34. Dowd KA, Netski DM, Wang XH, Cox AL, Ray SC (2009) Selection pressure from neutralizing antibodies drives sequence evolution during acute infection with hepatitis C virus. Gastroenterology 136:2377–2386PubMedGoogle Scholar
  35. Ebinuma H, Nakamoto N, Li Y et al (2008) Identification and in vitro expansion of functional antigen-specific CD25+ FoxP3+ regulatory T cells in hepatitis C virus infection. J Virol 82:5043–5053PubMedGoogle Scholar
  36. Erickson AL, Kimura Y, Igarashi S et al (2001) The outcome of hepatitis C virus infection is predicted by escape mutaions in epitopes targeted by cytotoxic T lymphocytes. Immunity 15:885–895Google Scholar
  37. 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 207:2019–2031PubMedGoogle Scholar
  38. Farci P, Alter HJ, Wong DC et al (1994) Prevention of hepatitis C virus infection in chimpanzees after antibody- mediated in vitro neutralization. Proc Natl Acad Sci USA 91:7792–7796PubMedGoogle Scholar
  39. Farci P, Shimoda A, Wong D et al (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 93:15394–15399PubMedGoogle Scholar
  40. Fitzmaurice K, Petrovic D, Ramamurthy N et al (2011) Molecular footprints reveal the impact of the protective HLA-A*03 allele in hepatitis C virus infection. Gut 60:1563–1571PubMedGoogle Scholar
  41. Fleming VM, Harcourt G, Barnes E, Klenerman P (2010) Virological footprint of CD4+ T-cell responses during chronic hepatitis C virus infection. J Gen Virol 91:1396–1406PubMedGoogle Scholar
  42. Fofana I, Fafi-Kremer S, Carolla P et al (2012) Mutations that alter use of hepatitis C virus cell entry factors mediate escape from neutralizing antibodies. GastroenterologyGoogle Scholar
  43. Fuller MJ, Shoukry NH, Gushima T et al (2010) Selection-driven immune escape is not a significant factor in the failure of CD4 T cell responses in persistent hepatitis C virus infection. Hepatology 51:378–387PubMedGoogle Scholar
  44. Gerlach JT, Diepolder HM, Jung MC et al (1999) Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T- cell response in acute hepatitis C. Gastroenterology 117:933–941PubMedGoogle Scholar
  45. Golden-Mason L, Palmer B, Klarquist J, Mengshol JA, Castelblanco N, Rosen HR (2007) Upregulation of PD-1 expression on circulating and intrahepatic hepatitis C virus-specific CD8+ T cells associated with reversible immune dysfunction. J Virol 81:9249–9258PubMedGoogle Scholar
  46. Golden-Mason L, Palmer BE, Kassam N et al (2009) Negative immune regulator Tim-3 is overexpressed on T cells in hepatitis C virus infection and its blockade rescues dysfunctional CD4+ and CD8+ T cells. J Virol 83:9122–9130PubMedGoogle Scholar
  47. Goulder PJ, Watkins DI (2008) Impact of MHC class I diversity on immune control of immunodeficiency virus replication. Nat Rev Immunol 8:619–630PubMedGoogle Scholar
  48. Grafmueller S, Billerbeck E, Blum HE, Neumann-Haefelin C, Thimme R (2012) Differential antigen specificity of hepatitis C virus-specific interleukin 17- and interferon gamma-producing CD8 (+) T cells during chronic infection. J Infect Dis 205:1142–1146PubMedGoogle Scholar
  49. Grakoui A, Shoukry NH, Woollard DJ et al (2003) HCV persistence and immune evasion in the absence of memory T cell help. Science 302:659–662PubMedGoogle Scholar
  50. Gruener NH, Gerlach TJ, Jung MC et al (2000) Association of hepatitis C virus-specific CD8+ T cells with viral clearance in acute hepatitis C. J Infect Dis 181:1528–1536Google Scholar
  51. Hall CH, Kassel R, Tacke RS, Hahn YS (2010) HCV+ hepatocytes induce human regulatory CD4+ T cells through the production of TGF-beta. PLoS One 5:e12154PubMedGoogle Scholar
  52. Heeg MH, Ulsenheimer A, Gruner NH et al (2009) FOXP3 expression in hepatitis C virus-specific CD4+ T cells during acute hepatitis C. Gastroenterology 137(1280–1288):1281–1286Google Scholar
  53. Hraber P, Kuiken C, Yusim K (2007) Evidence for human leukocyte antigen heterozygote advantage against hepatitis C virus infection. Hepatology 46:1713–1721PubMedGoogle Scholar
  54. Isogawa M, Furuichi Y, Chisari FV (2005) Oscillating CD8(+) T cell effector functions after antigen recognition in the liver. Immunity 23:53–63PubMedGoogle Scholar
  55. Itose I, Kanto T, Kakita N et al (2009) Enhanced ability of regulatory T cells in chronic hepatitis C patients with persistently normal alanine aminotransferase levels than those with active hepatitis. J Viral Hepat 16:844–852PubMedGoogle Scholar
  56. Jo J, Aichele U, Kersting N et al (2009) Analysis of CD8+ T-cell-mediated inhibition of hepatitis C virus replication using a novel immunological model. Gastroenterology 136:1391–1401PubMedGoogle Scholar
  57. Jo J, Bengsch B, Seigel B et al (2012) Low perforin expression of early differentiated HCV-specific CD8+ T cells limits their hepatotoxic potential. J HepatolGoogle Scholar
  58. Kaplan DE, Sugimoto K, Newton K et al (2007) Discordant role of CD4 T-cell response relative to neutralizing antibody and CD8 T-cell responses in acute hepatitis C. Gastroenterology 132:654–666PubMedGoogle Scholar
  59. Kasprowicz V, Kang YH, Lucas M et al (2010) Hepatitis C virus (HCV) sequence variation induces an HCV-specific T-cell phenotype analogous to spontaneous resolution. J Virol 84:1656–1663PubMedGoogle Scholar
  60. Kawashima Y, Pfafferott K, Frater J et al (2009) Adaptation of HIV-1 to human leukocyte antigen class I. Nature 458:641–645PubMedGoogle Scholar
  61. Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677–704PubMedGoogle Scholar
  62. Kiepiela P, Leslie AJ, Honeyborne I et al (2004) Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA. Nature 432:769–775PubMedGoogle Scholar
  63. Kim AY, Kuntzen T, Timm J et al (2011) Spontaneous control of HCV is associated with expression of HLA-B*57 and preservation of targeted epitopes. Gastroenterology 140:686–696PubMedGoogle Scholar
  64. Kimura Y, Gushima T, Rawale S, Kaumaya P, Walker CM (2005) Escape mutations alter proteasome processing of major histocompatibility complex class I-restricted epitopes in persistent hepatitis C virus infection. J Virol 79:4870–4876PubMedGoogle Scholar
  65. Krishnadas DK, Li W, Kumar R, Tyrrell DL, Agrawal B (2010) HCV-core and NS3 antigens play disparate role in inducing regulatory or effector T cells in vivo: implications for viral persistence or clearance. Vaccine 28:2104–2114PubMedGoogle Scholar
  66. Kuniholm MH, Kovacs A, Gao X et al (2010) Specific human leukocyte antigen class I and II alleles associated with hepatitis C virus viremia. Hepatology 51:1514–1522PubMedGoogle Scholar
  67. Lange CM, Roomp K, Dragan A et al (2010) HLA class I allele associations with HCV genetic variants in patients with chronic HCV genotypes 1a or 1b infection. J Hepatol 53:1022–1028PubMedGoogle Scholar
  68. Langhans B, Braunschweiger I, Arndt S et al (2010) Core-specific adaptive regulatory T-cells in different outcomes of hepatitis C. Clin Sci (Lond) 119:97–109Google Scholar
  69. Lechner F, Wong DK, Dunbar PR et al (2000) Analysis of successful immune responses in persons infected with hepatitis C virus. J Exp Med 191:1499–1512PubMedGoogle Scholar
  70. Li S, Floess S, Hamann A et al (2009) Analysis of FOXP3+ regulatory T cells that display apparent viral antigen specificity during chronic hepatitis C virus infection. PLoS Pathog 5:e1000707PubMedGoogle Scholar
  71. Logvinoff C, Major ME, Oldach D et al (2004) Neutralizing antibody response during acute and chronic hepatitis C virus infection. Proc Natl Acad Sci USA 101:10149–10154PubMedGoogle Scholar
  72. Lucas M, Ulsenheimer A, Pfafferot K et al (2007) Tracking virus-specific CD4+ T cells during and after acute hepatitis C virus infection. PLoS One 2:e649PubMedGoogle Scholar
  73. Manigold T, Shin EC, Mizukoshi E et al (2006) Foxp3+ CD4+ CD25+ T cells control virus-specific memory T cells in chimpanzees that recovered from hepatitis C. Blood 107:4424–4432PubMedGoogle Scholar
  74. McKiernan SM, Hagan R, Curry M et al (2004) Distinct MHC class I and II alleles are associated with hepatitis C viral clearance, originating from a single source. Hepatology 40:108–114PubMedGoogle Scholar
  75. McMahan RH, Golden-Mason L, Nishimura MI et al (2010) Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocyte-directed in vitro cytotoxicity. J Clin Invest 120:4546–4557PubMedGoogle Scholar
  76. McMichael AJ (2007) Triple bypass: complicated paths to HIV escape. J Exp Med 204:2785–2788PubMedGoogle Scholar
  77. Meyer-Olson D, Shoukry NH, Brady KW et al (2004) Limited T cell receptor diversity of HCV-specific T cell responses is associated with CTL escape. J Exp Med 200:307–319PubMedGoogle Scholar
  78. Missale G, Bertoni R, Lamonaca V et al (1996) Different clinical behaviors of acute hepatitis C virus infection are associated with different vigor of the anti-viral cell-mediated immune response. J Clin Invest 98:706–714PubMedGoogle Scholar
  79. Nakamoto N, Cho H, Shaked A et al (2009) Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade. PLoS Pathog 5:e1000313PubMedGoogle Scholar
  80. Nakamoto N, Kaplan DE, Coleclough J et al (2008) Functional restoration of HCV-specific CD8 T cells by PD-1 blockade is defined by PD-1 expression and compartmentalization. Gastroenterology 134(1927–1937):1921–1922Google Scholar
  81. Netski DM, Mosbruger T, Depla E et al (2005) Humoral immune response in acute hepatitis C virus infection. Clin Infect Dis 41:667–675PubMedGoogle Scholar
  82. Neumann-Haefelin C, Timm J, Spangenberg HC et al (2008a) Virological and immunological determinants of intrahepatic virus-specific CD8+ T-cell failure in chronic hepatitis C virus infection. Hepatology 47:1824–1836PubMedGoogle Scholar
  83. Neumann-Haefelin C, Frick DN, Wang JJ et al (2008b) Analysis of the evolutionary forces in an immunodominant CD8 epitope in hepatitis C virus at a population level. J Virol 82:3438–3451PubMedGoogle Scholar
  84. Neumann-Haefelin C, McKiernan S, Ward S et al (2006) Dominant influence of an HLA-B27 restricted CD8+ T cell response in mediating HCV clearance and evolution. Hepatology 43:563–572PubMedGoogle Scholar
  85. Neumann-Haefelin C, Oniangue-Ndza C, Kuntzen T et al (2011) Human leukocyte antigen B27 selects for rare escape mutations that significantly impair hepatitis C virus replication and require compensatory mutations. Hepatology 54:1157–1166PubMedGoogle Scholar
  86. Northfield JW, Kasprowicz V, Lucas M et al (2008) CD161 expression on hepatitis C virus-specific CD8+ T cells suggests a distinct pathway of T cell differentiation. Hepatology 47:396–406PubMedGoogle Scholar
  87. Oniangue-Ndza C, Kuntzen T, Kemper M et al (2011) Compensatory mutations restore the replication defects caused by cytotoxic T lymphocyte escape mutations in hepatitis C virus polymerase. J Virol 85:11883–11890PubMedGoogle Scholar
  88. Penna A, Pilli M, Zerbini A et al (2007) Dysfunction and functional restoration of HCV-specific CD8 responses in chronic hepatitis C virus infection. Hepatology 45:588–601PubMedGoogle Scholar
  89. Pestka JM, Zeisel MB, Blaser E et al (2007) Rapid induction of virus-neutralizing antibodies and viral clearance in a single-source outbreak of hepatitis C. Proc Natl Acad Sci USA 104:6025–6030PubMedGoogle Scholar
  90. Radziewicz H, Ibegbu CC, Hon H et al (2008) 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 82:9808–9822PubMedGoogle Scholar
  91. Radziewicz H, Ibegbu CC, Fernandez ML et al (2007) Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of PD-1 and low levels of CD127 expression. J Virol 81:2545–2553PubMedGoogle Scholar
  92. Raghuraman S, Park H, Osburn WO, Winkelstein E, Edlin BR, Rehermann B (2012) Spontaneous clearance of chronic hepatitis C virus infection is associated with appearance of neutralizing antibodies and reversal of T-cell exhaustion. J Infect Dis 205:763–771PubMedGoogle Scholar
  93. Rauch A, James I, Pfafferott K et al (2009) Divergent adaptation of hepatitis C virus genotypes 1 and 3 to human leukocyte antigen-restricted immune pressure. Hepatology 50:1017–1029PubMedGoogle Scholar
  94. Ray SC, Fanning L, Wang XH, Netski DM, Kenny-Walsh E, Thomas DL (2005) Divergent and convergent evolution after a common-source outbreak of hepatitis C virus. J Exp Med 201:1753–1759PubMedGoogle Scholar
  95. Raziorrouh B, Ulsenheimer A, Schraut W et al (2011) Inhibitory molecules that regulate expansion and restoration of HCV-specific CD4+ T cells in patients with chronic infection. Gastroenterology 141(4): 1422–1431, e1421–1426Google Scholar
  96. Riezu-Boj JI, Larrea E, Aldabe R et al (2010) Hepatitis C virus induces the expression of CCL17 and CCL22 chemokines that attract regulatory T cells to the site of infection. J Hepatol 54(3):422–431PubMedGoogle Scholar
  97. Ruhl M, Knuschke T, Schewior K et al (2011) CD8+ T-cell response promotes evolution of hepatitis C virus nonstructural proteins. Gastroenterology 140:2064–2073PubMedGoogle Scholar
  98. Rushbrook SM, Ward SM, Unitt E, Vowler SL, Lucas M, Klenerman P, Alexander GJ (2005) Regulatory T cells suppress in vitro proliferation of virus-specific CD8+ T cells during persistent hepatitis C virus infection. J Virol 79:7852–7859PubMedGoogle Scholar
  99. Rutebemberwa A, Ray SC, Astemborski J et al (2008) High-programmed death-1 levels on hepatitis C virus-specific T cells during acute infection are associated with viral persistence and require preservation of cognate antigen during chronic infection. J Immunol 181:8215–8225PubMedGoogle Scholar
  100. Sabo MC, Luca VC, Prentoe J et al (2011) Neutralizing monoclonal antibodies against hepatitis C virus E2 protein bind discontinuous epitopes and inhibit infection at a postattachment step. J Virol 85:7005–7019PubMedGoogle Scholar
  101. Schlaphoff V, Lunemann S, Suneetha PV et al (2011) Dual function of the NK cell receptor 2B4 (CD244) in the regulation of HCV-specific CD8+ T cells. PLoS Pathog 7:e1002045PubMedGoogle Scholar
  102. Schmidt J, Thimme R, Neumann-Haefelin C (2011) Host genetics in immune-mediated hepatitis C virus clearance. Biomark Med 5:155–169PubMedGoogle Scholar
  103. Schulze zur Wiesch J, Ciuffreda D, Lewis-Ximenez L et al (2012) Broadly directed virus-specific CD4+ T cell responses are primed during acute hepatitis C infection, but rapidly disappear from human blood with viral persistence. J Exp Med 209:61–75PubMedGoogle Scholar
  104. Schulze zur Wiesch J, Lauer GM, Day CL et al (2005) Broad repertoire of the CD4+ Th cell response in spontaneously controlled hepatitis C virus infection includes dominant and highly promiscuous epitopes. J Immunol 175:3603–3613PubMedGoogle Scholar
  105. Seifert U, Liermann H, Racanelli V et al (2004) Hepatitis C virus mutation affects proteasomal epitope processing. J Clin Invest 114:250–259PubMedGoogle Scholar
  106. Shin EC, Park SH, Demino M et al (2011) Delayed induction, not impaired recruitment, of specific CD8(+) T cells causes the late onset of acute hepatitis C. Gastroenterology 141(2):686–695, 695 e681Google Scholar
  107. Shoukry NH, Grakoui A, Houghton M, Chien DY, Ghrayeb J, Reimann KA, Walker CM (2003) Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection. J Exp Med 197:1645–1655PubMedGoogle Scholar
  108. Smyk-Pearson S, Golden-Mason L, Klarquist J et al (2008) Functional suppression by FoxP3+ CD4+ CD25 (high) regulatory T cells during acute hepatitis C virus infection. J Infect Dis 197:46–57PubMedGoogle Scholar
  109. Soderholm J, Ahlen G, Kaul A et al (2006) Relation between viral fitness and immune escape within the hepatitis C virus protease. Gut 55:266–274PubMedGoogle Scholar
  110. Spangenberg HC, Viazov S, Kersting N et al (2005) Intrahepatic CD8(+) T-cell failure during chronic hepatitis C virus infection. Hepatology 42:828–837PubMedGoogle Scholar
  111. Sturm N, Thelu MA, Camous X et al (2010) Characterization and role of intra-hepatic regulatory T cells in chronic hepatitis C pathogenesis. J Hepatol 53:25–35PubMedGoogle Scholar
  112. Sugimoto K, Ikeda F, Stadanlick J, Nunes FA, Alter HJ, Chang KM (2003) Suppression of HCV-specific T cells without differential hierarchy demonstrated ex vivo in persistent HCV infection. Hepatology 38:1437–1448PubMedGoogle Scholar
  113. Tester I, Smyk-Pearson S, Wang P et al (2005) Immune evasion versus recovery after acute hepatitis C virus infection from a shared source. J Exp Med 201:1725–1731PubMedGoogle Scholar
  114. 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 194:1395–1406PubMedGoogle Scholar
  115. Thimme R, Bukh J, Spangenberg HC et al (2002) Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease. Proc Natl Acad Sci USA 99:15661–15668PubMedGoogle Scholar
  116. Thio CL, Gao X, Goedert JJ et al (2002) HLA-Cw*04 and hepatitis C virus persistence. J Virol 76:4792–4797PubMedGoogle Scholar
  117. Timm J, Lauer GM, Kavanagh DG et al (2004) CD8 epitope escape and reversion in acute HCV infection. J Exp Med 200:1593–1604PubMedGoogle Scholar
  118. Timm J, Li B, Daniels MG et al (2007) Human leukocyte antigen-associated sequence polymorphisms in hepatitis C virus reveal reproducible immune responses and constraints on viral evolution. Hepatology 46:339–349PubMedGoogle Scholar
  119. Timpe JM, Stamataki Z, Jennings A et al (2008) Hepatitis C virus cell-cell transmission in hepatoma cells in the presence of neutralizing antibodies. Hepatology 47:17–24PubMedGoogle Scholar
  120. Ulsenheimer A, Lucas M, Seth NP et al (2006) Transient immunological control during acute hepatitis C virus infection: ex vivo analysis of helper T-cell responses. J Viral Hepat 13:708–714PubMedGoogle Scholar
  121. Urbani S, Amadei B, Cariani E, Fisicaro P, Orlandini A, Missale G, Ferrari C (2005) The impairment of CD8 responses limits the selection of escape mutations in acute hepatitis C virus infection. J Immunol 175:7519–7529PubMedGoogle Scholar
  122. von Hahn T, Yoon JC, Alter H, Rice CM, Rehermann B, Balfe P, McKeating JA (2007) Hepatitis C virus continuously escapes from neutralizing antibody and T-cell responses during chronic infection in vivo. Gastroenterology 132:667–678Google Scholar
  123. Ward SM, Fox BC, Brown PJ et al (2007) Quantification and localisation of FOXP3+ T lymphocytes and relation to hepatic inflammation during chronic HCV infection. J Hepatol 47:316–324PubMedGoogle Scholar
  124. Wedemeyer H, He XS, Nascimbeni M et al (2002) Impaired effector function of hepatitis C virus-specific CD8+ T cells in chronic hepatitis C virus infection. J Immunol 169:3447–3458PubMedGoogle Scholar
  125. Weiner A, Erickson AL, Kansopon J et al (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

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Department of Medicine IIUniversity of FreiburgFreiburgGermany

Personalised recommendations