Adaptive immune response during hepatitis C virus infection

World Journal of Gastroenterology

Volumn 20, Issue 13, 2014, Pages 3418-3430

  Larrubia, Juan Ramón ^a,b   Moreno Cubero, Elia ^a   Lokhande, Megha Uttam ^a   García Garzón, Silvia ^a   Lázaro, Alicia ^a   Miquel, Joaquín ^a   Perna, Cristian ^a   Sanz de Villalobos, Eduardo ^a  

^a HOSPITAL UNIVERSITARIO DE GUADALAJARA   (Spain)

^b UNIVERSITY OF ALCALÁ   (Spain)

Author keywords

Adaptive immune response; Anergy; Apoptosis; Chemotaxis; Hepatitis C; Hepatitis c virus escape mutations; Hepatitis C virus specific cytotoxic T cells; Hepatitis C virus specific T helper cells; T regs

Indexed keywords

ALANINE AMINOTRANSFERASE; CHEMOKINE; CYTOKINE; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4 ANTIBODY; GAMMA INTERFERON; HLA B27 ANTIGEN; IMMUNOGLOBULIN; INTERLEUKIN 2; KIDNEY INJURY MOLECULE 1; STAT PROTEIN; T LYMPHOCYTE RECEPTOR; TRANSCRIPTION FACTOR FOXP3; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR ALPHA; VIRUS PROTEIN; ANTIBODY; EPITOPE;

ADAPTIVE IMMUNITY; ANTIBODY RESPONSE; ANTIBODY TITER; ANTIGEN PRESENTING CELL; APOPTOSIS; ARTICLE; CELL CYCLE REGULATION; CELL DIFFERENTIATION; CELLULAR IMMUNITY; CHRONIC LIVER DISEASE; DISEASE ASSOCIATION; DISEASE COURSE; HEPATITIS C; HUMAN; HUMORAL IMMUNITY; IMMUNOLOGICAL TOLERANCE; IMMUNOMODULATION; IMMUNOSTIMULATION; LYMPHOCYTIC INFILTRATION; NONHUMAN; PROTEIN EXPRESSION; REGULATORY MECHANISM; REGULATORY T LYMPHOCYTE; T LYMPHOCYTE ACTIVATION; VIRUS LOAD; VIRUS PATHOGENESIS; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL SEPARATION; CYTOLOGY; FLOW CYTOMETRY; GENE DELETION; IMMUNOLOGY; INFLAMMATION; METABOLISM; MUTATION; PHENOTYPE;

ADAPTIVE IMMUNITY; ANTIBODIES; APOPTOSIS; CD4-POSITIVE T-LYMPHOCYTES; CD8-POSITIVE T-LYMPHOCYTES; CELL SEPARATION; CHEMOKINES; EPITOPES; FLOW CYTOMETRY; GENE DELETION; HEPATITIS C; HUMANS; IMMUNITY, CELLULAR; IMMUNITY, HUMORAL; INFLAMMATION; MUTATION; PHENOTYPE;

EID: 84897568492     PISSN: 10079327     EISSN: 22192840     Source Type: Journal    
DOI: 10.3748/wjg.v20.i13.3418     Document Type: Article

References (107)

1. Nowak MA, Bangham CR. Population dynamics of immune responses to persistent viruses. Science 1996; 272: 74-79 [PMID: 8600540 DOI: 10.1126/science.272.5258.74]
2. Larrubia JR, Benito-Martínez S, Miquel-Plaza J, Sanz-de-Villalobos E, González-Mateos F, Parra T. Cytokines - their pathogenic and therapeutic role in chronic viral hepatitis. Rev Esp Enferm Dig 2009; 101: 343-351 [PMID: 19527080 DOI: 10.4321/S1130-01082009000500006]
3. Choudhuri K, Kearney A, Bakker TR, van der Merwe PA. Immunology: how do T cells recognize antigen? Curr Biol 2005; 15: R382-R385 [PMID: 15916940 DOI: 10.1016/ j.cub.2005.05.001]
4. Appay V, van Lier RA, Sallusto F, Roederer M. Phenotype and function of human T lymphocyte subsets: consensus and issues. Cytometry A 2008; 73: 975-983 [PMID: 18785267 DOI: 10.1002/cyto.a.20643]
5. Guidotti LG, Chisari FV. Immunobiology and pathogenesis of viral hepatitis. Annu Rev Pathol 2006; 1: 23-61 [PMID: 18039107 DOI: 10.1146/annurev.pathol.1.110304.100230]
6. Edwards VC, Tarr AW, Urbanowicz RA, Ball JK. The role of neutralizing antibodies in hepatitis C virus infection. J Gen Virol 2012; 93: 1-19 [PMID: 22049091 DOI: 10.1099/ vir.0.035956-0]
7. Semmo N, Lucas M, Krashias G, Lauer G, Chapel H, Klenerman P. Maintenance of HCV-specific T-cell responses in antibody-deficient patients a decade after early therapy. Blood 2006; 107: 4570-4571 [PMID: 16717132 DOI: 10.1182/ blood-2005-11-4522]
8. Dustin LB, Rice CM. Flying under the radar: the immunobiology of hepatitis C. Annu Rev Immunol 2007; 25: 71-99 [PMID: 17067278 DOI: 10.1146/annurev.immunol.25.022106.141602]
9. Lechner F, Gruener NH, Urbani S, Uggeri J, Santantonio T, Kammer AR, Cerny A, Phillips R, Ferrari C, Pape GR, Klenerman P. CD8+ T lymphocyte responses are induced during acute hepatitis C virus infection but are not sustained. Eur J Immunol 2000; 30: 2479-2487 [PMID: 11009080]
10. Lechner F, Wong DK, Dunbar PR, Chapman R, Chung RT, Dohrenwend P, Robbins G, Phillips R, Klenerman P, Walker BD. Analysis of successful immune responses in persons infected with hepatitis C virus. J Exp Med 2000; 191: 1499-1512 [PMID: 10790425 DOI: 10.1084/jem.191.9.1499]
11. Logvinoff C, Major ME, Oldach D, Heyward S, Talal A, Balfe P, Feinstone SM, Alter H, Rice CM, McKeating JA. Neutralizing antibody response during acute and chronic hepatitis C virus infection. Proc Natl Acad Sci USA 2004; 101: 10149-10154 [PMID: 15220475 DOI: 10.1073/pnas.0403519101]
12. Thimme R, Bukh J, Spangenberg HC, Wieland S, Pemberton J, Steiger C, Govindarajan S, Purcell RH, Chisari FV. Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease. Proc Natl Acad Sci USA 2002; 99: 15661-15668 [PMID: 12441397 DOI: 10.1073/ pnas.202608299]
13. Farci P, Shimoda A, Wong D, Cabezon T, De Gioannis D, Strazzera A, Shimizu Y, Shapiro M, Alter HJ, Purcell RH. 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 1996; 93: 15394-15399 [PMID: 8986822 DOI: 10.1073/pnas.93.26.15394]
14. Pestka JM, Zeisel MB, Bläser E, Schürmann P, Bartosch B, Cosset FL, Patel AH, Meisel H, Baumert J, Viazov S, Rispeter K, Blum HE, Roggendorf M, Baumert TF. Rapid induction of virus-neutralizing antibodies and viral clearance in a single-source outbreak of hepatitis C. Proc Natl Acad Sci USA 2007; 104: 6025-6030 [PMID: 17392433 DOI: 10.1073/ pnas.0607026104]
15. Dowd KA, Netski DM, Wang XH, Cox AL, Ray SC. Selection pressure from neutralizing antibodies drives sequence evolution during acute infection with hepatitis C virus. Gastroenterology 2009; 136: 2377-2386 [PMID: 19303013 DOI: 10.1053/j.gastro.2009.02.080]
16. Zeisel MB, Cosset FL, Baumert TF. Host neutralizing responses and pathogenesis of hepatitis C virus infection. Hepatology 2008; 48: 299-307 [PMID: 18508291 DOI: 10.1002/ hep.22307]
17. Racanelli V, Frassanito MA, Leone P, Galiano M, De Re V, Silvestris F, Dammacco F. Antibody production and in vitro behavior of CD27-defined B-cell subsets: persistent hepatitis C virus infection changes the rules. J Virol 2006; 80: 3923-3934 [PMID: 16571809 DOI: 10.1128/JVI.80.8.3923-3934.2006]
18. Agnello V, De Rosa FG. Extrahepatic disease manifestations of HCV infection: some current issues. J Hepatol 2004; 40: 341-352 [PMID: 14739110 DOI: 10.1016/j.jhep.2003.10.009]
19. Amarapurkar DN, Amarapurkar AD. Extrahepatic manifestations of viral hepatitis. Ann Hepatol 2002; 1: 192-195 [PMID: 15280806]
20. Manns MP, Rambusch EG. Autoimmunity and extrahepatic manifestations in hepatitis C virus infection. J Hepatol 1999; 31 Suppl 1: 39-42 [PMID: 10622558 DOI: 10.1016/ S0168-8278(99)80372-9]
21. Zhang P, Zhong L, Struble EB, Watanabe H, Kachko A, Mihalik K, Virata-Theimer ML, Alter HJ, Feinstone S, Major M. Depletion of interfering antibodies in chronic hepatitis C patients and vaccinated chimpanzees reveals broad cross-genotype neutralizing activity. Proc Natl Acad Sci USA 2009; 106: 7537-7541 [PMID: 19380744 DOI: 10.1073/pnas.0902749106]
22. Bassett SE, Thomas DL, Brasky KM, Lanford RE. Viral persistence, antibody to E1 and E2, and hypervariable region 1 sequence stability in hepatitis C virus-inoculated chimpanzees. J Virol 1999; 73: 1118-1126 [PMID: 9882313]
23. Thimme R, Lohmann V, Weber F. A target on the move: innate and adaptive immune escape strategies of hepatitis C virus. Antiviral Res 2006; 69: 129-141 [PMID: 16413618 DOI: 10.1016/j.antiviral.2005.12.001]
24. 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: 1395-1406 [PMID: 11714747 DOI: 10.1084/jem.194.10.1395]
25. Bowen DG, Walker CM. Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature 2005; 436: 946-952 [PMID: 16107834 DOI: 10.1038/nature04079]
26. Shin EC, Seifert U, Kato T, Rice CM, Feinstone SM, Kloetzel PM, Rehermann B. Virus-induced type I IFN stimulates generation of immunoproteasomes at the site of infection. J Clin Invest 2006; 116: 3006-3014 [PMID: 17039255 DOI: 10.1172/ JCI29832]
27. Rehermann B. Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence. J Clin Invest 2009; 119: 1745-1754 [PMID: 19587449 DOI: 10.1172/JCI39133]
28. Diepolder HM, Zachoval R, Hoffmann RM, Wierenga EA, Santantonio T, Jung MC, Eichenlaub D, Pape GR. Possible mechanism involving T-lymphocyte response to non-structural protein 3 in viral clearance in acute hepatitis C virus infection. Lancet 1995; 346: 1006-1007 [PMID: 7475549 DOI: 10.1016/S0140-6736(95)91691-1]
29. Missale G, Bertoni R, Lamonaca V, Valli A, Massari M, Mori C, Rumi MG, Houghton M, Fiaccadori F, Ferrari C. 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: 706-714 [PMID: 8698862 DOI: 10.1172/JCI118842]
30. Kapadia SB, Barth H, Baumert T, McKeating JA, Chisari FV. Initiation of hepatitis C virus infection is dependent on cholesterol and cooperativity between CD81 and scavenger receptor B type I. J Virol 2007; 81: 374-383 [PMID: 17050612 DOI: 10.1128/JVI.01134-06]
31. Urbani S, Amadei B, Fisicaro P, Tola D, Orlandini A, Sacchelli L, Mori C, Missale G, Ferrari C. Outcome of acute hepatitis C is related to virus-specific CD4 function and maturation of antiviral memory CD8 responses. Hepatology 2006; 44: 126-139 [PMID: 16799989 DOI: 10.1002/hep.21242]
32. Gerlach JT, Diepolder HM, Jung MC, Gruener NH, Schraut WW, Zachoval R, Hoffmann R, Schirren CA, Santantonio T, Pape GR. Recurrence of hepatitis C virus after loss of virusspecific CD4(+) T-cell response in acute hepatitis C. Gastroenterology 1999; 117: 933-941 [PMID: 10500077 DOI: 10.1016/ S0016-5085(99)70353-7]
33. Nascimbeni M, Mizukoshi E, Bosmann M, Major ME, Mihalik K, Rice CM, Feinstone SM, Rehermann B. Kinetics of CD4+ and CD8+ memory T-cell responses during hepatitis C virus rechallenge of previously recovered chimpanzees. J Virol 2003; 77: 4781-4793 [PMID: 12663785 DOI: 10.1128/ JVI.77.8.4781-4793.2003]
34. Smyk-Pearson S, Tester IA, Klarquist J, Palmer BE, Pawlotsky JM, Golden-Mason L, Rosen HR. Spontaneous recovery in acute human hepatitis C virus infection: functional T-cell thresholds and relative importance of CD4 help. J Virol 2008; 82: 1827-1837 [PMID: 18045940 DOI: 10.1128/ JVI.01581-07]
35. Francavilla V, Accapezzato D, De Salvo M, Rawson P, Cosimi O, Lipp M, Cerino A, Cividini A, Mondelli MU, Barnaba V. Subversion of effector CD8+ T cell differentiation in acute hepatitis C virus infection: exploring the immunological mechanisms. Eur J Immunol 2004; 34: 427-437 [PMID: 14768047 DOI: 10.1002/eji.200324539]
36. Kaplan DE, Sugimoto K, Newton K, Valiga ME, Ikeda F, Aytaman A, Nunes FA, Lucey MR, Vance BA, Vonderheide RH, Reddy KR, McKeating JA, Chang KM. Discordant role of CD4 T-cell response relative to neutralizing antibody and CD8 T-cell responses in acute hepatitis C. Gastroenterology 2007; 132: 654-666 [PMID: 17258733 DOI: 10.1053/ j.gastro.2006.11.044]
37. Bowen DG, Shoukry NH, Grakoui A, Fuller MJ, Cawthon AG, Dong C, Hasselschwert DL, Brasky KM, Freeman GJ, Seth NP, Wucherpfennig KW, Houghton M, Walker CM. Variable patterns of programmed death-1 expression on fully functional memory T cells after spontaneous resolution of hepatitis C virus infection. J Virol 2008; 82: 5109-5114 [PMID: 18337576 DOI: 10.1128/JVI.00060-08]
38. Keir ME, Francisco LM, Sharpe AH. PD-1 and its ligands in T-cell immunity. Curr Opin Immunol 2007; 19: 309-314 [PMID: 17433872 DOI: 10.1016/j.coi.2007.04.012]
39. Nakamoto N, Kaplan DE, Coleclough J, Li Y, Valiga ME, Kaminski M, Shaked A, Olthoff K, Gostick E, Price DA, Freeman GJ, Wherry EJ, Chang KM. Functional restoration of HCV-specific CD8 T cells by PD-1 blockade is defined by PD-1 expression and compartmentalization. Gastroenterology 2008; 134: 1927-1937, 1937e1-e2 [PMID: 18549878 DOI: 10.1053/j.gastro.2008.02.033]
40. Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol 2007; 8: 239-245 [PMID: 17304234 DOI: 10.1038/ni1443]
41. Urbani S, Amadei B, Tola D, Massari M, Schivazappa S, Missale G, Ferrari C. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. J Virol 2006; 80: 11398-11403 [PMID: 16956940 DOI: 10.1128/JVI.01177-06]
42. Rahman F, Heller T, Sobao Y, Mizukoshi E, Nascimbeni M, Alter H, Herrine S, Hoofnagle J, Liang TJ, Rehermann B. Effects of antiviral therapy on the cellular immune response in acute hepatitis C. Hepatology 2004; 40: 87-97 [PMID: 15239090 DOI: 10.1002/hep.20253]
43. Veerapu NS, Raghuraman S, Liang TJ, Heller T, Rehermann B. Sporadic reappearance of minute amounts of hepatitis C virus RNA after successful therapy stimulates cellular immune responses. Gastroenterology 2011; 140: 676-685.e1 [PMID: 21040725 DOI: 10.1053/j.gastro.2010.10.048]
44. Yerly D, Heckerman D, Allen TM, Chisholm JV, Faircloth K, Linde CH, Frahm N, Timm J, Pichler WJ, Cerny A, Brander C. Increased cytotoxic T-lymphocyte epitope variant crossrecognition and functional avidity are associated with hepatitis C virus clearance. J Virol 2008; 82: 3147-3153 [PMID: 18184704 DOI: 10.1128/JVI.02252-07]
45. Chang KM, Rehermann B, McHutchison JG, Pasquinelli C, Southwood S, Sette A, Chisari FV. Immunological significance of cytotoxic T lymphocyte epitope variants in patients chronically infected by the hepatitis C virus. J Clin Invest 1997; 100: 2376-2385 [PMID: 9410918 DOI: 10.1172/ JCI119778]
46. Timm J, Li B, Daniels MG, Bhattacharya T, Reyor LL, Allgaier R, Kuntzen T, Fischer W, Nolan BE, Duncan J, Schulze zur Wiesch J, Kim AY, Frahm N, Brander C, Chung RT, Lauer GM, Korber BT, Allen TM. Human leukocyte antigenassociated sequence polymorphisms in hepatitis C virus reveal reproducible immune responses and constraints on viral evolution. Hepatology 2007; 46: 339-349 [PMID: 17559151 DOI: 10.1002/hep.21702]
47. Penna A, Pilli M, Zerbini A, Orlandini A, Mezzadri S, Sacchelli L, Missale G, Ferrari C. Dysfunction and functional restoration of HCV-specific CD8 responses in chronic hepatitis C virus infection. Hepatology 2007; 45: 588-601 [PMID: 17326153 DOI: 10.1002/hep.21541]
48. Larrubia JR, Lokhande MU, García-Garzón S, Miquel J, González-Praetorius A, Parra-Cid T, Sanz-de-Villalobos E. Persistent hepatitis C virus (HCV) infection impairs HCVspecific cytotoxic T cell reactivity through Mcl-1/Bim imbalance due to CD127 down-regulation. J Viral Hepat 2013; 20: 85-94 [PMID: 23301543 DOI: 10.1111/j.1365-2893.2012.01618.x]
49. Alatrakchi N, Graham CS, van der Vliet HJ, Sherman KE, Exley MA, Koziel MJ. Hepatitis C virus (HCV)-specific CD8+ cells produce transforming growth factor beta that can suppress HCV-specific T-cell responses. J Virol 2007; 81: 5882-5892 [PMID: 17376924 DOI: 10.1128/JVI.02202-06]
50. 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: 1437-1448 [PMID: 14647055 DOI: 10.1016/j.hep.2003.09.026]
51. Tester I, Smyk-Pearson S, Wang P, Wertheimer A, Yao E, Lewinsohn DM, Tavis JE, Rosen HR. Immune evasion versus recovery after acute hepatitis C virus infection from a shared source. J Exp Med 2005; 201: 1725-1731 [PMID: 15939788 DOI: 10.1084/jem.20042284]
52. 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: 1753-1759 [PMID: 15939791 DOI: 10.1084/ jem.20050122]
53. Timm J, Lauer GM, Kavanagh DG, Sheridan I, Kim AY, Lucas M, Pillay T, Ouchi K, Reyor LL, Schulze zur Wiesch J, Gandhi RT, Chung RT, Bhardwaj N, Klenerman P, Walker BD, Allen TM. CD8 epitope escape and reversion in acute HCV infection. J Exp Med 2004; 200: 1593-1604 [PMID: 15611288 DOI: 10.1084/jem.20041006]
54. Cox AL, Mosbruger T, Mao Q, Liu Z, Wang XH, Yang HC, Sidney J, Sette A, Pardoll D, Thomas DL, Ray SC. Cellular immune selection with hepatitis C virus persistence in humans. J Exp Med 2005; 201: 1741-1752 [PMID: 15939790 DOI: 10.1084/jem.20050121]
55. 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: 104-112 [PMID: 15962289 DOI: 10.1002/ hep.20749]
56. Dazert E, Neumann-Haefelin C, Bressanelli S, Fitzmaurice K, Kort J, Timm J, McKiernan S, Kelleher D, Gruener N, Tavis JE, Rosen HR, Shaw J, Bowness P, Blum HE, Klenerman P, Bartenschlager R, Thimme R. 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 2009; 119: 376-386 [PMID: 19139562 DOI: 10.1172/ JCI36587]
57. Neumann-Haefelin C, McKiernan S, Ward S, Viazov S, Spangenberg HC, Killinger T, Baumert TF, Nazarova N, Sheridan I, Pybus O, von Weizsäcker F, Roggendorf M, Kelleher D, Klenerman P, Blum HE, Thimme R. Dominant influence of an HLA-B27 restricted CD8+ T cell response in mediating HCV clearance and evolution. Hepatology 2006; 43: 563-572 [PMID: 16496339 DOI: 10.1002/hep.21049]
58. Kim AY, Kuntzen T, Timm J, Nolan BE, Baca MA, Reyor LL, Berical AC, Feller AJ, Johnson KL, Schulze zur Wiesch J, Robbins GK, Chung RT, Walker BD, Carrington M, Allen TM, Lauer GM. Spontaneous control of HCV is associated with expression of HLA-B 57 and preservation of targeted epitopes. Gastroenterology 2011; 140: 686-696.e1 [PMID: 20875418 DOI: 10.1053/j.gastro.2010.09.042]
59. Fitzmaurice K, Petrovic D, Ramamurthy N, Simmons R, Merani S, Gaudieri S, Sims S, Dempsey E, Freitas E, Lea S, McKiernan S, Norris S, Long A, Kelleher D, Klenerman P. Molecular footprints reveal the impact of the protective HLA-A*03 allele in hepatitis C virus infection. Gut 2011; 60: 1563-1571 [PMID: 21551190 DOI: 10.1136/gut.2010.228403]
60. Piazzolla G, Tortorella C, Schiraldi O, Antonaci S. Relationship between interferon-gamma, interleukin-10, and interleukin-12 production in chronic hepatitis C and in vitro effects of interferon-alpha. J Clin Immunol 2000; 20: 54-61 [PMID: 10798608]
61. Accapezzato D, Francavilla V, Paroli M, Casciaro M, Chircu LV, Cividini A, Abrignani S, Mondelli MU, Barnaba V. Hepatic expansion of a virus-specific regulatory CD8(+) T cell population in chronic hepatitis C virus infection. J Clin Invest 2004; 113: 963-972 [PMID: 15057302 DOI: 10.1172/JCI20515]
62. Dolganiuc A, Chang S, Kodys K, Mandrekar P, Bakis G, Cormier M, Szabo G. Hepatitis C virus (HCV) core proteininduced, monocyte-mediated mechanisms of reduced IFNalpha and plasmacytoid dendritic cell loss in chronic HCV infection. J Immunol 2006; 177: 6758-6768 [PMID: 17082589]
63. Duramad O, Fearon KL, Chan JH, Kanzler H, Marshall JD, Coffman RL, Barrat FJ. IL-10 regulates plasmacytoid dendritic cell response to CpG-containing immunostimulatory sequences. Blood 2003; 102: 4487-4492 [PMID: 12946990 DOI: 10.1182/blood-2003-07-2465]
64. Abel M, Sène D, Pol S, Bourlière M, Poynard T, Charlotte F, Cacoub P, Caillat-Zucman S. Intrahepatic virus-specific IL-10-producing CD8 T cells prevent liver damage during chronic hepatitis C virus infection. Hepatology 2006; 44: 1607-1616 [PMID: 17133491 DOI: 10.1002/hep.21438]
65. Radziewicz H, Ibegbu CC, Hon H, Bédard N, Bruneau J, Workowski KA, Knechtle SJ, Kirk AD, Larsen CP, Shoukry NH, Grakoui A. Transient CD86 expression on hepatitis C virus-specific CD8+ T cells in acute infection is linked to sufficient IL-2 signaling. J Immunol 2010; 184: 2410-2422 [PMID: 20100932 DOI: 10.4049/jimmunol.0902994]
66. Shevach EM. Mechanisms of foxp3+ T regulatory cellmediated suppression. Immunity 2009; 30: 636-645 [PMID: 19464986 DOI: 10.1016/j.immuni.2009.04.010]
67. Manigold T, Shin EC, Mizukoshi E, Mihalik K, Murthy KK, Rice CM, Piccirillo CA, Rehermann B. Foxp3+CD4+CD25+ T cells control virus-specific memory T cells in chimpanzees that recovered from hepatitis C. Blood 2006; 107: 4424-4432 [PMID: 16478885 DOI: 10.1182/blood-2005-09-3903]
68. Boettler T, Spangenberg HC, Neumann-Haefelin C, Panther E, Urbani S, Ferrari C, Blum HE, von Weizsäcker F, Thimme R. 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: 7860-7867 [PMID: 15919940 DOI: 10.1128/JVI.79.12.7860-7867.2005]
69. Cabrera R, Tu Z, Xu Y, Firpi RJ, Rosen HR, Liu C, Nelson DR. An immunomodulatory role for CD4(+)CD25(+) regulatory T lymphocytes in hepatitis C virus infection. Hepatology 2004; 40: 1062-1071 [PMID: 15486925 DOI: 10.1002/ hep.20454]
70. Rushbrook SM, Ward SM, Unitt E, Vowler SL, Lucas M, Klenerman P, Alexander GJ. Regulatory T cells suppress in vitro proliferation of virus-specific CD8+ T cells during persistent hepatitis C virus infection. J Virol 2005; 79: 7852-7859 [PMID: 15919939 DOI: 10.1128/JVI.79.12.7852-7859.2005]
71. Franceschini D, Paroli M, Francavilla V, Videtta M, Morrone S, Labbadia G, Cerino A, Mondelli MU, Barnaba V. PD-L1 negatively regulates CD4+CD25+Foxp3+ Tregs by limiting STAT-5 phosphorylation in patients chronically infected with HCV. J Clin Invest 2009; 119: 551-564 [PMID: 19229109 DOI: 10.1172/JCI36604]
72. Protzer U, Maini MK, Knolle PA. Living in the liver: hepatic infections. Nat Rev Immunol 2012; 12: 201-213 [PMID: 22362353 DOI: 10.1038/nri3169]
73. Wherry EJ. T cell exhaustion. Nat Immunol 2011; 12: 492-499 [PMID: 21739672 DOI: 10.1038/ni.2035]
74. Larrubia JR, Benito-Martínez S, Miquel J, Calvino M, Sanzde-Villalobos E, Parra-Cid T. Costimulatory molecule programmed death-1 in the cytotoxic response during chronic hepatitis C. World J Gastroenterol 2009; 15: 5129-5140 [PMID: 19891011 DOI: 10.3748/wjg.15.5129]
75. Larrubia JR, Benito-Martínez S, Miquel J, Calvino M, Sanz-de-Villalobos E, González-Praetorius A, Albertos S, García-Garzón S, Lokhande M, Parra-Cid T. Bim-mediated apoptosis and PD-1/PD-L1 pathway impair reactivity of PD1(+)/CD127(-) HCV-specific CD8(+) cells targeting the virus in chronic hepatitis C virus infection. Cell Immunol 2011; 269: 104-114 [PMID: 21481848 DOI: 10.1016/ j.cellimm.2011.03.01]
76. Golden-Mason L, Palmer B, Klarquist J, Mengshol JA, Castelblanco N, Rosen HR. Upregulation of PD-1 expression on circulating and intrahepatic hepatitis C virus-specific CD8+ T cells associated with reversible immune dysfunction. J Virol 2007; 81: 9249-9258 [PMID: 17567698 DOI: 10.1128/JVI.00409-07]
77. Radziewicz H, Ibegbu CC, Fernandez ML, Workowski KA, Obideen K, Wehbi M, Hanson HL, Steinberg JP, Masopust D, Wherry EJ, Altman JD, Rouse BT, Freeman GJ, Ahmed R, Grakoui A. 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: 2545-2553 [PMID: 17182670 DOI: 10.1128/ JVI.02021-06]
78. Nakamoto N, Cho H, Shaked A, Olthoff K, Valiga ME, Kaminski M, Gostick E, Price DA, Freeman GJ, Wherry EJ, Chang KM. Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade. PLoS Pathog 2009; 5: e1000313 [PMID: 19247441 DOI: 10.1371/journal.ppat.1000313]
79. Schlaphoff V, Lunemann S, Suneetha PV, Jaroszewicz J, Grabowski J, Dietz J, Helfritz F, Bektas H, Sarrazin C, Manns MP, Cornberg M, Wedemeyer H. Dual function of the NK cell receptor 2B4 (CD244) in the regulation of HCV-specific CD8+ T cells. PLoS Pathog 2011; 7: e1002045 [PMID: 21625589 DOI: 10.1371/journal.ppat.1002045]
80. Golden-Mason L, Palmer BE, Kassam N, Townshend-Bulson L, Livingston S, McMahon BJ, Castelblanco N, Kuchroo V, Gretch DR, Rosen HR. 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 2009; 83: 9122-9130 [PMID: 19587053 DOI: 10.1128/ JVI.00639-09]
81. Bengsch B, Seigel B, Ruhl M, Timm J, Kuntz M, Blum HE, Pircher H, Thimme R. 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 2010; 6: e1000947 [PMID: 20548953 DOI: 10.1371/journal. ppat.1000947]
82. Larrubia JR, Lokhande MU, García-Garzón S, Miquel J, Subirá D, Sanz-de-Villalobos E. Role of T cell death in maintaining immune tolerance during persistent viral hepatitis. World J Gastroenterol 2013; 19: 1877-1889 [PMID: 23569333 DOI: 10.3748/wjg.v19.i12.1877]
83. Aubert RD, Kamphorst AO, Sarkar S, Vezys V, Ha SJ, Barber DL, Ye L, Sharpe AH, Freeman GJ, Ahmed R. Antigenspecific CD4 T-cell help rescues exhausted CD8 T cells during chronic viral infection. Proc Natl Acad Sci USA 2011; 108: 21182-21187 [PMID: 22160724 DOI: 10.1073/ pnas.1118450109]
84. Han S, Asoyan A, Rabenstein H, Nakano N, Obst R. Role of antigen persistence and dose for CD4+ T-cell exhaustion and recovery. Proc Natl Acad Sci USA 2010; 107: 20453-20458 [PMID: 21059929 DOI: 10.1073/pnas.1008437107]
85. Welsh RM, Waggoner SN. NK cells controlling virusspecific T cells: Rheostats for acute vs. persistent infections. Virology 2013; 435: 37-45 [PMID: 23217614 DOI: 10.1016/ j.virol.2012.10.005]
86. Waggoner SN, Cornberg M, Selin LK, Welsh RM. Natural killer cells act as rheostats modulating antiviral T cells. Nature 2012; 481: 394-398 [PMID: 22101430 DOI: 10.1038/nature10624]
87. Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 1994; 76: 301-314 [PMID: 7507411 DOI: 10.1016/0092-8674(94)90337-9]
88. Larrubia JR, Calvino M, Benito S, Sanz-de-Villalobos E, Perna C, Pérez-Hornedo J, González-Mateos F, García-Garzón S, Bienvenido A, Parra T. The role of CCR5/CXCR3 expressing CD8+ cells in liver damage and viral control during persistent hepatitis C virus infection. J Hepatol 2007; 47: 632-641 [PMID: 17560677 DOI: 10.1016/j.jhep.2007.04.009]
89. Shields PL, Morland CM, Salmon M, Qin S, Hubscher SG, Adams DH. Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis C-infected liver. J Immunol 1999; 163: 6236-6243 [PMID: 10570316]
90. Bièche I, Asselah T, Laurendeau I, Vidaud D, Degot C, Paradis V, Bedossa P, Valla DC, Marcellin P, Vidaud M. Molecular profiling of early stage liver fibrosis in patients with chronic hepatitis C virus infection. Virology 2005; 332: 130-144 [PMID: 15661146 DOI: 10.1016/j.virol.2004.11.009]
91. Apolinario A, Majano PL, Alvarez-Pérez E, Saez A, Lozano C, Vargas J, García-Monzón C. Increased expression of T cell chemokines and their receptors in chronic hepatitis C: relationship with the histological activity of liver disease. Am J Gastroenterol 2002; 97: 2861-2870 [PMID: 12425561 DOI: 10.1111/j.1572-0241.2002.07054.x]
92. Apolinario A, Diago M, Lo Iacono O, Lorente R, Pérez C, Majano PL, Clemente G, García-Monzón C. Increased circulating and intrahepatic T-cell-specific chemokines in chronic hepatitis C: relationship with the type of virological response to peginterferon plus ribavirin combination therapy. Aliment Pharmacol Ther 2004; 19: 551-562 [PMID: 14987324 DOI: 10.1111/j.1365-2036.2004.01872.x]
93. Apolinario A, Majano PL, Lorente R, Núñez O, Clemente G, García-Monzón C. Gene expression profile of T-cell-specific chemokines in human hepatocyte-derived cells: evidence for a synergistic inducer effect of cytokines and hepatitis C virus proteins. J Viral Hepat 2005; 12: 27-37 [PMID: 15655045 DOI: 10.1111/j.1365-2893.2005.00540.x]
94. Sillanpää M, Kaukinen P, Melén K, Julkunen I. Hepatitis C virus proteins interfere with the activation of chemokine gene promoters and downregulate chemokine gene expression. J Gen Virol 2008; 89: 432-443 [PMID: 18198374 DOI: 10.1099/vir.0.83316-0]
95. Larrubia JR, Benito-Martínez S, Calvino M, Sanz-de-Villalobos E, Parra-Cid T. Role of chemokines and their receptors in viral persistence and liver damage during chronic hepatitis C virus infection. World J Gastroenterol 2008; 14: 7149-7159 [PMID: 19084927 DOI: 10.3748/wjg.14.7149]
96. Sprengers D, van der Molen RG, Kusters JG, Kwekkeboom J, van der Laan LJ, Niesters HG, Kuipers EJ, De Man RA, Schalm SW, Janssen HL. Flow cytometry of fine-needleaspiration biopsies: a new method to monitor the intrahepatic immunological environment in chronic viral hepatitis. J Viral Hepat 2005; 12: 507-512 [PMID: 16108766 DOI: 10.1111/ j.1365-2893.2005.00626.x]
97. Harvey CE, Post JJ, Palladinetti P, Freeman AJ, Ffrench RA, Kumar RK, Marinos G, Lloyd AR. Expression of the chemokine IP-10 (CXCL10) by hepatocytes in chronic hepatitis C virus infection correlates with histological severity and lobular inflammation. J Leukoc Biol 2003; 74: 360-369 [PMID: 12949239 DOI: 10.1189/jlb.0303093]
98. Helbig KJ, Ruszkiewicz A, Semendric L, Harley HA, McColl SR, Beard MR. Expression of the CXCR3 ligand I-TAC by hepatocytes in chronic hepatitis C and its correlation with hepatic inflammation. Hepatology 2004; 39: 1220-1229 [PMID: 15122750 DOI: 10.1002/hep.20167]
99. Kusano F, Tanaka Y, Marumo F, Sato C. Expression of C-C chemokines is associated with portal and periportal inflammation in the liver of patients with chronic hepatitis C. Lab Invest 2000; 80: 415-422 [PMID: 10744077 DOI: 10.1038/labinvest. 3780046]
100. Bertoletti A, Maini MK. Protection or damage: a dual role for the virus-specific cytotoxic T lymphocyte response in hepatitis B and C infection? Curr Opin Microbiol 2000; 3: 387-392 [PMID: 10972499 DOI: 10.1016/S1369-5274(00)00109-0]
101. Friedman SL. Liver fibrosis -- from bench to bedside. J Hepatol 2003; 38 Suppl 1: S38-S53 [PMID: 12591185 DOI: 10.1016/ S0168-8278(02)00429-4]
102. Barnes E, Harcourt G, Brown D, Lucas M, Phillips R, Dusheiko G, Klenerman P. The dynamics of T-lymphocyte responses during combination therapy for chronic hepatitis C virus infection. Hepatology 2002; 36: 743-754 [PMID: 12198669 DOI: 10.1053/jhep.2002.35344]
103. Pilli M, Zerbini A, Penna A, Orlandini A, Lukasiewicz E, Pawlotsky JM, Zeuzem S, Schalm SW, von Wagner M, Germanidis G, Lurie Y, Esteban JI, Haagmans BL, Hezode C, Lagging M, Negro F, Homburger Y, Neumann AU, Ferrari C, Missale G. HCV-specific T-cell response in relation to viral kinetics and treatment outcome (DITTO-HCV project). Gastroenterology 2007; 133: 1132-1143 [PMID: 17919489 DOI: 10.1053/j.gastro.2007.06.059]
104. Kamal SM, Fehr J, Roesler B, Peters T, Rasenack JW. Peginterferon alone or with ribavirin enhances HCV-specific CD4 T-helper 1 responses in patients with chronic hepatitis C. Gastroenterology 2002; 123: 1070-1083 [PMID: 12360469 DOI: 10.1053/gast.2002.36045]
105. Fisicaro P, Valdatta C, Massari M, Loggi E, Ravanetti L, Urbani S, Giuberti T, Cavalli A, Vandelli C, Andreone P, Missale G, Ferrari C. Combined blockade of programmed death-1 and activation of CD137 increase responses of human liver T cells against HBV, but not HCV. Gastroenterology 2012; 143: 1576-1585.e4 [PMID: 22929808 DOI: 10.1053/ j.gastro.2012.08.041]
106. Ferrari C. Therapeutic vaccination for hepatitis C: can protective T-cell responses be restored after prolonged antigen exposure? Gastroenterology 2008; 134: 1601-1604 [PMID: 18471527 DOI: 10.1053/j.gastro.2008.03.016]
107. Zhang Y, Liu Y, Moxley KM, Golden-Mason L, Hughes MG, Liu T, Heemskerk MH, Rosen HR, Nishimura MI. Transduction of human T cells with a novel T-cell receptor confers anti-HCV reactivity. PLoS Pathog 2010; 6: e1001018 [PMID: 20686664 DOI: 10.1371/journal.ppat.1001018]