Cellular immunity and acute hepatitis C infection

Current Pharmaceutical Design

Volumn 14, Issue 17, 2008, Pages 1666-1677

  Fitzmaurice, K ^a   Klenerman, Paul ^b  

^a ST JAMES S HOSPITAL   (Ireland)

^b UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

Acute hepatitis C; Cell mediated; Escape mutation; Immunology; T cell

Indexed keywords

GAMMA INTERFERON; HLA A ANTIGEN; HLA DQ ANTIGEN; HLA DR ANTIGEN; INTERLEUKIN 10; INTERLEUKIN 2; INTERLEUKIN 4;

ACUTE HEPATITIS; ANTIINFLAMMATORY ACTIVITY; ANTIVIRAL ACTIVITY; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELLULAR IMMUNITY; CHRONIC HEPATITIS; CYTOKINE RELEASE; HEPATITIS C; HLA SYSTEM; HOST RESISTANCE; HUMAN; IMMUNOGENETICS; IMMUNOREGULATION; INFECTION RESISTANCE; INTERFERON PRODUCTION; LYMPHOCYTE FUNCTION; MOLECULAR EVOLUTION; NONHUMAN; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; REVIEW; T LYMPHOCYTE ACTIVATION; VIRUS MUTATION; VIRUS VIRULENCE;

ACUTE DISEASE; CD4-POSITIVE T-LYMPHOCYTES; CHRONIC DISEASE; HEPACIVIRUS; HEPATITIS C; HISTOCOMPATIBILITY ANTIGENS CLASS I; HUMANS; IMMUNITY, CELLULAR; VIRUS REPLICATION;

EID: 47349083365     PISSN: 13816128     EISSN: None     Source Type: Journal    
DOI: 10.2174/138161208784746806     Document Type: Review

References (132)

1. Thimme R, Oldach D, Chang KM, Steiger C, Ray SC, Chisari FV. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med 2001; 194: 1395-406.
2. Farci P, Alter HJ, Wong D, Miller RH, Shih JW, Jett B, et al. A long-term study of hepatitis C virus replication in non-A, non-B hepatitis. N Engl J Med 1991; 325: 98-104.
3. Bowen DG, Walker CM. Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature 2005; 436: 946-52.
4. Shoukry NH, Cawthon AG, Walker CM. Cell-mediated immunity and the outcome of hepatitis C virus infection. Annu Rev Microbiol 2004; 58: 391-424.
5. Thimme R, Bukh J, Spangenberg HC, Wieland S, Pemberton J, Steiger C, et al. Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease. Proc Natl Acad Sci USA 2002; 99: 15661-8.
6. Cooper S, Erickson AL, Adams EJ, Kansopon J, Weiner AJ, Chien DY, et al. Analysis of a successful immune response against hepatitis C virus. Immunity 1999; 10: 439-49.
7. Grakoui A, Shoukry NH, Woollard, DJ, Han JH, Hanson HL, Ghrayeb J, et al. HCV persistence and immune evasion in the absence of memory T cell help. Science 2003; 302: 659-62.
8. Diepolder HM, Zachoval R, Hoffmann RM, Wierenga EA, Santantonio T, Jung MC, et al. Possible mechanism involving T-lymphocyte response to non-structural protein 3 in viral clearance in acute hepatitis C virus infection. Lancet 1995; 346: 1006-7.
9. Missale G, Bertoni R, Lamonaca V, Valli A, Massari M, Mori C, et al. 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 1996; 98: 706-14.
10. Urbani S, Amadei B, Fisicaro P, Tola D, Orlandini A, Sacchelli L, et al. Outcome of acute hepatitis C is related to virus-specific CD4 function and maturation of antiviral memory CD8 responses. Hepatology 2006; 44: 126-39.
11. Gerlach JT, Diepolder HM, Jung MC, Gruener NH, Schraut WW, Zachoval R, et al. Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T-cell response in acute hepatitis C. Gastroenterology 1999; 117: 933-41.
12. Day CL, Lauer GM, Robbins GK, McGovern B, Wurcel AG, Gandhi RT, et al. Broad specificity of virus-specific CD4+ T-helper-cell responses in resolved hepatitis C virus infection. J Virol 2002; 76: 12584-95
13. Lechner F, Wong DK, Dunbar PR, Chapman R, Chung RT, Dohrenwend P, et al. Analysis of successful immune responses in persons infected with hepatitis C virus. J Exp Med 2000; 191: 1499-512.
14. Rosen HR, Miner C, Sasaki AW, Lewinsohn DM, Conrad AJ, Bakke A, et al. Frequencies of HCV-specific effector CD4+ T cells by flow cytometry: Correlation with clinical disease stages. Hepatology 2002; 35: 190-8.
15. Takaki A, Wiese M, Maertens G, Depla E, Seifert U, Liebetrau A, et al. Cellular immune responses persist and humoral responses decrease two decades after recovery from a single-source outbreak of hepatitis C. Nat Med 2000; 6: 578-82.
16. Tester I, Smyk-Pearson S, Wang P, Wertheimer A, Yao E, Lewinsohn DM, et al. Immune evasion versus recovery after acute hepatitis C virus infection from a shared source. J Exp Med 2005; 201: 1725-31.
17. Gerlach JT, Ulsenheimer A, Gruner NH, Jung MC, Schraut W, Schirren CA, et al. Minimal T-cell-stimulatory sequences and spectrum of HLA restriction of immunodominant CD4t T-cell epitopes within hepatitis C virus NS3 and NS4 proteins. J Virol 2005; 79: 12425-33.
18. Shoukry NH, Sidney J, Sette A, Walker CM. Conserved hierarchy of helper T cell responses in a chimpanzee during primary and secondary hepatitis C virus infections. J Immunol 2004; 172: 483-92.
19. Whitmire JK, Asano MS, Murali-Krishna K, Suresh M, Ahmed R, Long-term CD4 Th1 and Th2 memory following acute lymphocytic choriomeningitis virus infection. J Virol 1998; 72: 8281-8.
20. Varga SM, Welsh RM. Detection of a high frequency of virus-specific CD4+ T cells during acute infection with lymphocytic choriomeningitis virus. J Immunol 1998; 161: 3215-8.
21. Tsai SL, Liaw YF, Chen MH, Huang CY, Kuo GC. Detection of type 2-like T-helper cells in hepatitis C virus infection: Implications for hepatitis C virus chronicity. Hepatology 1997; 25: 449-58.
22. Ulsenheimer A, Lucas M, Seth NP, Tilman Gerlach J, Gruener NH, Loughry A, et al. Transient immunological control during acute hepatitis C virus infection: Ex vivo analysis of helper T-cell responses. J Viral Hepat 2006; 13: 708-14.
23. Ulsenheimer A, Gerlach JT, Gruener NH, Jung MC, Schirren CA, Schraut W, et al. Detection of functionally altered hepatitis C virus-specific CD4 T cells in acute and chronic hepatitis C. Hepatology 2003; 37: 1189-98.
24. Day CL, Seth NP, Lucas M, Appel H, Gauthier L, Lauer GM, et al. Ex vivo analysis of human memory CD4 T cells specific for hepatitis C virus using MHC class II tetramers. J Clin Invest 2003; 112: 831-42
25. Lucas M, Ulsenheimer A, Pfafferot K, Heeg MH, Gaudieri S, Gruner N, et al. Tracking virus-specific CD4+ T cells during and after acute hepatitis C virus infection. PLoS ONE 2007; 2: E649.
26. Semmo N, Day CL, Ward SM, Lucas M, Harcourt G, Loughry A, et al. Preferential loss of IL-2-secreting CD4+ T helper cells in chronic HCV infection. Hepatology 2005; 41: 1019-28.
27. Semmo N, Krashias G, Willberg C, Klenerman P. Analysis of the relationship between cytokine secretion and proliferative capacity in hepatitis C virus infection. J Viral Hepat 2007; 14: 492-502.
28. Waggoner SN, Hall CH, Hahn YS. HCV core protein interaction with gC1q receptor inhibits Th1 differentiation of CD4+ T cells via suppression of dendritic; cell IL-12 production. J Leukoc Biol 2007; 82: 1407-19.
29. Alric L, Fort M, Izopet J, Vinel JP, Charlet JP, Selves J, et al. Genes of the major histocompabbility complex class II influence the outcome of hepatitis C virus infection. Gastroenterology 1997; 113: 1675-81.
30. Cramp ME, Carucci P, Underhill J, Naoumov NV, William R, Donaldson PT. Association between HLA class II genotype and spontaneous clearance of hepatitis C viraemia. J Hepatol 1998; 29: 207-13.
31. Mangia A, Gentile R, Cascavilla I, Margaglione M, Villani MR, Stella F, et al. HLA class II favors clearance of HCV infection and progression of the chronic liver damage. J Hepatol 1999; 30: 984-9.
32. Minton EJ, Smillie D, Neal KR, Irving WL, Underwood JC, James V. Association between MHC class II alleles and clearance of circulating hepatitis C virus. Members of the Trent Hepatitis C Virus Study Group. J Infect Dis 1998; 178: 39-44.
33. Thuraz M, Yallop R, Goldin R, Trepo C, Thomas HC. Influence of MHC class II genotype on outcome of infection with hepatitis C virus. The HENCORE group. Hepatitis C European Network for Cooperative Research. Lancet 1999; 354: 2119-24.
34. Thio CL, Thomas DL, Goedert JJ, Vlahov D, Nelson KE, Hilgartner MW, et al. Racial differences in HLA chiss II associations with hepatitis C virus outcomes. J Infect Dis 2001; 184: 16-21.
35. Zavaglia C, Martinetti M, Silini E, Bottelli R, Daielli C, Asti M, et al. Association between HLA class II alleles and protection from or susceptibility to chronic hepatitis C. J Hepatol 1998; 28: 1-7.
36. Yenigun A, Durupinar B. Decreased frequency of the HLA-DRB1*11 allele in patients with chronic hepatitis C virus infection. J Virol 2002; 76: 1787-9.
37. Scotto G, Fazio V, D'Alessandro G, Monno L, Saracino A, Palumbo E, et al. Association between HLA class II antigens and hepatitis C virus infection. J Biol Regul Homeost Agents 2003; 17: 316-21.
38. Yee LJ. Host genetic determinants in hepatitis C virus infection. Genes Immun 2004; 5: 237-45.
39. Hong X, Yu RB, Sun NX, Wang B, Xu YC, Wu GL. Human leukocyte antigen class II DQB1*0301, DRB1*1101 alleles and spontaneous clearance of hepatitis C virus infection: A meta-analysis. World J Gastroenterol 2005; 11: 7302-7.
40. Barrett S, Ryan E, Crowe J. Association of the HLA-DRB1*01 allele with spontaneous viral clearance in an Irish cohort infected with hepatitis C virus via contaminated anti-D immunoglobulin. J Hepatol 1999; 30: 979-83.
41. Fanning LJ, Levis J, Kenny-Walsh E, Wynne F, Whelton M, Shanahan F. Viral clearance in hepatitis C (1b) infection: Relationship with human leukocyte antigen class II in a homogeneous population. Hepatology 2000; 31: 1334-7.
42. McKiernan SM, Hagan R, Churry M, McDonald GS, Nolan N, Crowley J, et al. The MHC is a major determinant of viral status, but not fibrotic stage, in individuals infected with hepatitis C. Gastroenterology 2000; 118: 1124-30.
43. McKiernan SM, Hagan R, Curry M, McDonald GS, Kelly A, Nolan N, et al. Distinct MHC class I and II alleles are associated with hepatitis C viral clearance, originating from a single source. Hepatology 2004; 40: 108-14.
44. Barrett S, Goh J, Coughlan B, Ryan E, Stewart S, Cockram A, et al. The natural course of hepatitis C virus infection after 22 years in a unique homogenous cohort: Spontaneous viral clearance and chronic HCV infection. Gut 2001; 49: 423-30.
45. Harcourt G, Hellier S, Bunco M, Satsangi J, Collier J, Chapman R, et al. Effect of HLA class II genotype on T helper lymphocyte responses and viral control in hepatitis C virus infection. J Viral Hepat 2001; 8: 174-9.
46. Diepolder HM, Gerlach JT, Zachoval R, Hoffmann RM, Jung MC, Wierenga EA, et al. Immunodominant CD4+ T-cell epitope within nonstructural protein 3 in acute hepatitis C virus infection. J Virol 1997; 71: 6011-9.
47. Lamonaea V, Missale G, Urbani S, Pilli M, Boni C, Mori C, et al. Conserved hepatitis C virus sequences are highly immunogenic for CD4(+) T cells: Implications for vaccine development, Hepatology 1999; 30: 1088-98.
48. Neumann-Haefelin C, Blum HE, Chisari FV, Thimme R. T cell response in hepatitis C virus infection. J Clin Virol 2005; 32: 75-85.
49. Cox AL, Mosbruger T, Lauer GM, Pardoll D, Thomas DL, Ray SC. Comprehensive analyses of CD8+ T cell responses during longitudinal study of acute human hepatitis C. Hepatology 2005; 42: 104-12.
50. Lauer GM, Lucas M, Timm J, Ouchi K, Kim AY, Day CL, et al. Full-breadth analysis of CD8+ T-cell responses in acute hepatitis C virus infection and early therapy. J Virol 2005; 79: 12979-88.
51. Lechner F, Gruener NH, Urbani S, Uggeri J, Santantonio T, Kammer AR, et al. CD8+ T lymphocyte responses are induced during acute hepatitis C virus infection but are not sustained. Eur J Immunol 2000; 30: 2479-87.
52. Shoukry NH, Grakoui A, Houghton M, Chien DY, Ghrayeb J, Reimann KA, et al. Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection. J Exp Med 2003; 197: 1645-55
53. Gruener NH, Lechner F, Jung MC, Diepolder H, Gerlach T, Lauer G, et al. Sustained dysfunction of antiviral CD8+ T lymphocytes after infection with hepatitis C virus. J Virol 2001; 75: 5550-8.
54. Urbani S, Boni C, Missale G, Elia G, Cavallo C, Massari M, et al. Virus-specific CD8+ lymphocytes share the same effector-memory phenotype but exhibit fuctional differences acute hepatitis B and C. J Virol 2002; 76: 12423-34.
55. Major ME, Mihalik K, Puig M, Rehermann B, Nascimbeni M, Rice CM, et al. Previously infected and recovered chimpanzees exhibit rapid responses that control hepatitis C virus replication upon rechallenge. J Virol 2002; 76: 6586-95.
56. Bassett SE, Guerra B, Brasky K, Miskovsky E, Houghton M, Klimpel GR, et al. Protective immune response to hepatitis C virus in chimpanzees rechallenged following clearance of primary infection. Hopatology 2001; 33: 1479-87.
57. Rehermann B, Chang KK McHutchison JG, Kokka R, Houghton M, Chisari FV. Quantitative analysis: Of the peripheral blood cytotoxic T lymphocyte response in patients with chronic hepatitis C virus infection. J Clin Invest 1996; 98: 1432-40.
58. Wedemeyer H, He XS, Nascimbeni M, Davis AR, Greenberg HB, Hoofnagle JH, et al. Impaired effector function of hepatitis C virus-specific CD8+ T cells in chronic hepatitis C virus infection. J Immunol 2002; 169: 3447-58.
59. Lauer GM, Barnes E, Lucas M, Timm J, Ouchi K, Kim AY, et al. High resolution analysis of cellular immune responses in resolved and persistent hepatitis C virus infection. Gastroenterology 2004; 127: 924-36.
60. Koziel MJ, Dudley D, Afdhal N, Grakoui A, Rice CM, Choo QL, et al. HLA class I-restricted cytotoxic T lymphocytes specific for hepatitis C virus. Identification of multiple epitopes and charactetization of patterns of cytokine release. J Clin Invest 1995; 96: 2311-21.
61. Koziel Mi, Dudley D, Wong JT, Dienstag J, Houghton M, Ralston R, et al. Intrahepatic cytotoxic T lymphocytes specific for hepatitis C virus in persons with chronic hepatitis. J Immunol 1992; 149: 3339-44
62. Erickson AL, Kimura Y, Igarashi S, Eichelberger J, Houghton M, Sidney J, et al. The outcome of hepatitis C virus infection is predicted by escape mutations in epitopes targeted by cytotoxic T lymphocytes. Immunity 2001; 15: 883-95.
63. Urbani S, Amadei B, Fisicaro P, Pilli M, Missale G, Bertoletti A. et al. Heterologous T cell immunity in severe hepatitis C virus infection. J Exp Mod 2005; 201: 675-80.
64. Neumann-Haefelin C, McKiernan S, Ward S, Viazov S, Spangenberg HC, Killinger T, et al. Dominant influence of an HLA-B27 restricted CD8+ T cell response in mediating HCV clearance and evolution. Hepatology 2006; 43: 563-72.
65. Nelson DR, Marousis CG, Davis GL, Rice CM, Wong J, Houghton M, et al. The role of hepatitis C virus-specific cytotoxic T lymphocytes in chronic hepatitis C. J Immunol 1997; 158: 1473-81.
66. Wong DY, Dudley DD, Afdhal NH, Dienstag J, Rice CM, Wang L, et al. Liver-derived CTL in hepatitis C virus infection: Breadth and specificity of responses in a cohort of persons with chronic infection. J Immunol 1998; 160: 1479-88.
67. Hiroishi K, Kita H, Kojima M, Okamoto H, Moriyama T, Kaneko T, et al. Cytotoxic T lymphocyte response and viral load in hepatitis C virus infection. Hepatology 1997; 25: 705-12.
68. Kieforsauer S, Reiter C, Eisenburg J, Diepolder HM, Rieber EP, Riethmuller G, et al. Depletion of CD8+ T lymphocytes by murine monoclonal CD8 antibodies and restored specific T cell proliferation in vivo in a. patient with chronic hepatitis C. J Immunol 1997; 159: 4064-71.
69. Thio CL, Gao Y, Goedert JJ, Vlahov D, Nelson KE, Hilgartner MW, et al. HLA-Cw*04 and hepatitis C virus persistence. J Virol 2002; 76: 4792-7.
70. Chuang WC, Sarkodie F, Brown CJ, Owusu-Ofori S, Brown J, Li C, et al. Protective effect of HLA-B57 on HCV genotype 2 infection in a West African population. J Med Virol 2007; 79: 724-33.
71. Goulder PJ, Watkins DI. HIV and SIV CTL escape: Implications for vaccine design. Nat Rev Immunol 2004; 4: 630-40.
72. Khakoo SI, Thio CL, Martin MP, Brooks CR, Gao X, Astemborski J, et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science 2004; 305: 872-4.
73. Mehta SH, Cox A, Hoover DR, Wang XH, Mao Q, Ray S, et al. Protection against persistence of hepatitis C. Lancet 2002; 359: 1478-83.
74. Bowen DG, Walker CM. Mutational escape from CD8+ T cell immunity: HCV evolution from chimpanzees to man. J Exp Med 2005; 201: 1709-14.
75. Timm J, Lauer GM, Kavanagh DG, Sheridan I, Kim AY, Lucas M, et al. CD8 epitope escape and reversion in acute HCV infection. J Exp Med 2004; 200: 1593-604.
76. Gaudieri S, Rauch A, Park LP, Freitas E, Herrmann S, Jeffrey G, et al. Evidence of viml adaptation to HLA class I-restricted immune pressure in chronic hepatitis C virus infection. J Virol 2006; 80: 11094-104.
77. Timm J, Li B, Daniels MG, Bhattacharya T, Reyor LL, Allgaier R, et al. Human leukocyte antigen-associated sequence polymorphisms in hepatitis C virus reveal reproducible immune responses and constraints on viral evolution. Hepatology 2007; 46: 339-49.
78. Ray SC, Fanning L, Wang XH, Netski DM, Kenny-Walsh E, Thomas DL. Divergent and convergent evolution after a common-source outbreak of hepatitis C virus. J Exp Med 2005; 201: 1753-9.
79. Schneidewind A, Brockman MA, Yang R, Adam RI, Li B, Le Gall S, et al. Escape from the dominant HLA-B27-restrieted cytotoxic T-lymphocyte response in Gag is associated with a dramatic reduction in human immunodeficiency virus type 1 replication. J Virol 2007; 81: 12382-93.
80. Soderholm J, Ahlen G, Kaul A, Frelin L, Alheim M, Barnfield C, et al. Relation between viral fitness and immune escape within the hepatitis C virus protease. Gut 2006; 55: 266-74.
81. Klenerman P, Zirkkemagel RM. Original antigenic sin impairs cytotoxic T lymphocyte responses to viruses bearing variant epitopes. Nature 1998; 394: 482-5.
82. Leslie A, Kavanagh D, Honeyborne I, Pfafferott K, Edwards C, Pillay T, et al. Transmission and accumulation of CTL escape variants drive negative associations between HIV polymorphisms and HLA. J Exp Med 2005; 201: 891-902.
83. Eckels DD, Zhou H, Bian TH, Wang H. Identification of antigenic escape variants in an immunodominant epitope of hepatitis C virus. Int Immunol. 1999; 11: 577-83.
84. Wang H, Eckels DD. Mutations in immunodominant T cell epitopes derived from the nonstructural 3 protein of hepatitis C virus have the potential for generating escape variants that may have important consequences for T cell recognition. J Immunol 1999; 162: 4177-83.
85. Harcourt GC, Garrard S, Davenport MP, Edwards A, Phillips RE. HIV-1 variation diminished CD4 T lymphocyte recognition. J Exp Med 1998; 188: 1785-93.
86. Wang JH, Layden TJ, Eckels DD. Modulation of the peripheral T-Cell response by CD4 mutants of hepatitis C virus: Transition from a Th1 to a Th2 response. Hum Immunol 2003; 64: 662-73.
87. Harcourt GC, Lucas M, Sheridan I, Barnes E, Phillips R, Klenerman P. Longitudinal mapping of protective CD4+ T cell responses against HCV: analysis of fluctuating dominant and subdominent HLA-DR11 restricted epitopes. J Viral Hepat 2004; 11: 324-31.
88. Neumann-Haefelin C, Spangenberg HC, Blum HE, Thimme R. Host and viral factors contributing to CD8+ T cell failure in hepatitis C virus infection. World J Gastroenterol 2007; 13: 4839-47.
89. Anthony DD, Yonkers NL, Post AB, Asaad R, Heinzel FP, Lederman MM, et al. Selective impairments in dendritic cell-associated function distinguish hepatitis C virus and HIV infection. J Immunol 2004; 172: 4907-16.
90. Bain C, Fatmi A, Zoulim F, Zarski JP, Trepo C, Inchauspe G. Impaired allostimulatory function of dendritic cells in chronic hepatitis C infection. Gastroenterology 2001; 120: 512-24.
91. Kanto T, Hayashi N, Takehara T, Tatsumi T, Kuzushita N, Ito A, et al. Impaired allostimulatory capacity of peripheral blood dendritic cells recovered from hepatitis C virus-infected individuals. J Immunol 1999; 162: 5584-91.
92. Matloubian M, Concepcion RJ, Ahmed R. CD4+ T cells are required to sustain CD8+ cytotoxic T-ccll responses during chronic viral infection. J Virol 1994; 68: 8056-63.
93. Crispe IN. Hepatic T cells and liver tolerance. Nat Rev Immunol 2003; 3: 51-62.
94. Rollier C, Drexhage JA, Verstrepen BE, Verschoor EJ, Bontrop RE, Koopman G, et al. Chronic hepatitis C virus infection established and maintained in chimpanzees independent of dendritic cell impairment. Hepatology 2003; 38: 851-8.
95. Longman RS, Talal AH, Jacobson IM, Albert ML, Rice CM. Presence of functional dendritic cells in patients chronically infected with hepatitis C virus. Blood 2004; 103: 1026-9.
96. Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol 2003; 77: 4911-27.
97. McNeil AC, Shupert WL, Iyasere CA, Hallahan CW, Mican JA, Davey RT Jr, et al. High-level HIV-1 viremia suppresses viral antigen-specific CD4(+) T cell proliferation. Proc Natl Acad Sci USA 2001; 98: 13878-83.
98. Brooks DG, Teyton L, Oldstone MB, McGavern DB. Intrinsic functional dysregulation of CD4 T cells occurs rapidly following persistent viral infection. J Virol 2005; 79: 10514-27.
99. Moskophidis D, Lechner F, Pircher H, Zinkernagel RM. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature 1993; 362: 758-61.
100. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 2006; 439: 682-7.
101. Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 2006; 443: 350-4.
102. Urbani S, Amadei B, Tola D, Massari M, Schivazappa S, Missale G, et al. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. J Virol 2006; 80: 11398-403.
103. Radziewicz H, Ibegbu CC, Fernandez ML, Workowski KA, Obideen K, Wehbi M, et al. 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 2007; 81: 2545-53.
104. Kasprowicz V, Schulze Zur Wiesch J, Kuntzen T, Nolan BE, Longworth S, Berical A, et al. High PD-1 expression on HCV-specific CD8+ and CD4+ T cells during acute Hepatitis C irrespective of clinical outcome. J Virol 2008; 82: 3154-60.
105. Penna A, Pilli M, Zerbini A, Orlandini A, Mezzadri S, Sacchelli L, et al. Dysfunction and functional restoration of HCV-specific CD8 responses in chronic hepatitis C virus infection. Hepatology 2007; 45: 588-601.
106. Rigopoulou EI, Abbott WG, Haigh P, Naoumov NV. Blocking of interleukin-10 receptor - a novel approach to stimulate T-helper cell type 1 responses to hepatitis C virus. Clin Immunol 2005; 117: 57-64.
107. Wherry EJ, Ha SJ, Kaech SM, Haining WN, Sarkar S, Kalia V, et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 2007; 27: 670-84.
108. Manigold T, Racanelli V. T-cell regulation by CD4 regulatory T cells during hepatitis B and C virus infections: Facts and controversies. Lancet Infect Dis 2007; 7: 804-13.
109. Billerbeck E, Bottler T, Thimme R. Regulatory T cells in viral hepatitis. World J Gastroenterol 2007; 13: 4858-64.
110. MacDonald AJ, Duffy M, Brady MT, McKieman S, Hall W, Hegarty J, et al. CD4 T helper type 1 and regulatory T cells induced against the same epitopes on the core protein in hepatitis C virus-infected persons. J Infect Dis 2002; 185: 720-7.
111. Boettler T, Spangenberg HC, Neumann-Haefelin C, Panther E, Urbani S, Ferrari C, et al. 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 2005; 79: 7860-7
112. Cabrera R, Tu Z, Xu Y, Firpi RJ, Rosen HR, Liu C, et al. An immunomodulatory role for CD4(+)CD25(+) regulatory T lymphocytes in hepatitis C virus infection. Hepatology 2004; 40: 1062-71.
113. Sugimoto K, Ikeda F, Stadanlick J, Nunes FA, Alter HJ, Chang KM. Suppression of HCV-specific T cells without differential hierarchy demonstrated ex vivo in persistent HCV infection. Hepatology 2003; 38: 1437-48.
114. Rushbrook SM, Ward SM, Unitt E, Vowler SL, Lucas M, Klenerman P, et al. Regulatory T cells suppress in vitro proliferation of virus-specific CD8+ T cells during persistent hepatitis C virus infection. J Virol 2005; 79: 7852-9.
115. Ward SM, Fox BC, Brown PJ, Worthington J, Fox SB, Chapman RW, et al. Quantification and localisation of FOXP3+ T lymphocytes and relation to hepatic inflammation during chronic HCV infection. J Hepatol 2007; 47: 316-24.
116. Accapezzato D, Francavilla V, Paroli M, Casciaro M, Chircu LV, Cividini A, et al. Hepatic expansion of a virus-specific regulatory CD8(+) T cell population in chronic hepatitis C virus infection. J Clin Invest 2004; 113: 963-72.
117. Manigold T, Shin EC, Mizukoshi E, Mihalik K, Murthy KK, Rice CM, et al. Foxp3+CD4+CD25+ T cells control virus-specific memory T cells in chimpanzees that recovered from hepatitis C. Blood 2006; 107: 4424-32
118. Bolacchi F, Sinistro A, Ciaprini C, Derain F, Capozzi M, Carducci FC, et al. Increased hepatitis C virus (HCV)-specific CD4+CD25+ regulatory T lymphocytes and reduced HGV-specific CD4+ T cell response in HCV-infected patients with normal versus abnormal alanine aminotransferase levels. Clin Exp Immunol 2006; 144: 188-96.
119. Bowen DG, McCaughan GW, Bertolino P. Intrahepatic immunity: A tale of two sites? Trends Immunol 2005; 26: 512-7.
120. Schirren CA, Jung MC, Gerlach JT, Worzfeld T, Baretton G, Mamin M, et al. Liver-derived hepatitis C virus (HCV)-specific CD4(+) T cells recognize multiple HCV epitopes and produce interferon gamma. Hepatology 2000; 32: 597-603.
121. Penna A, Missale G, Lamonaca V, Pilli M, More C, Zanelli P, et al. Intrahepatic and circulating HLA class II-restricted, hepatitis C virus-specific T cells: Functional characterization in patients with chronic hepatitis C. Hepatology 2002; 35: 1225-36.
122. Watanabe T, Katsukura H, Chiba T, Kita T, Wakatsuki Y. Periportal and sinusoidal liver dendritic cells suppressing T helper type 1-mediated hepatitis. Gut 2007; 56: 1445-51.
123. Kittlesen DJ, Chianese-Bullock KA, Yao ZQ, Braciale TJ, Hahn YS. Interaction between complement receptor gC1qR and hepatitis C virus core protein inhibits T-lymphocyte proliferation. J Clin Invest 2000; 106: 1239-49.
124. Crotta S, Stilla A, Wack A, D'Andrea A, Nuti S, D'Oro U, et al. Inhibition of natural killer cells through engagement of CD81 by the major hepatitis C virus envelope protein. J Exp Med 2002; 195: 35-41
125. Dolganiuc A, Kodys K, Kopasz A, Marshall C, Do T, Romics L Jr, et al. Hepatitis C virus core and nonstructural protein 3 proteins induce pro- and anti-inflammatory cytokines and inhibit dendritic cell differentiation. J Immunol 2003; 170: 5615-24.
126. Brady MT, MacDonald AJ, Rowan AG, Mills KH. Hepatitis C virus non-structural protein 4 suppresses Th1 responses by stimulating EL-10 production from monocytes. Eur J Immunol 2003; 33: 3448-57.
127. Alric L, Fort M, Izopet J, Vinel JP, Bureau C, Sandre K, et al. Study of host- and virus-related factors associated with spontaneous hepatitis C virus clearance. Tissue Antigens 2000; 56: 154-8.
128. Vejbaesya S, Songsivilai S, Tanwandee T, Rachaibun S, Chantangpol R, Dharakul T. HLA association with hepatitis C virus infection. Hum Immunol 2000; 61: 348-53.
129. Fanning LJ, Kenny-Walsh E, Shanahan F. Persistence of hepatitis C virus in a white population: Associations with human leukocyte antigen class 1. Hum Immunol. 2004; 65: 745-51.
130. Amati L, Pepe M, Passeri ME, Mastronardi ML, Jirillo E, Covelli V. Toll-like receptor signaling mechanism involved in dendritic cell activation: Potential therapeutic control of T cell polarization. Curr Pharm Des 2006; 12(32): 4247-54.
131. Iruretagoyena MI, Wiesendanger M, Kalergis AM. The dendritic cell-T cell synapse as a determinant of autoimmune pathogenesis. Curr Pharm Des 2006; 12(2): 131-47.
132. Panyi G, Possani LD, Rodriguez de la Vega RC, Gaspar R, Varga Z. K+ channel blockers: Novel tools to inhibit T cell activation leading to specific immunosuppression. Curr Pharm Des 2006; 12(18): 2199-220.