Emerging concepts in immunity to hepatitis C virus infection

Journal of Clinical Investigation

Volumn 123, Issue 10, 2013, Pages 4121-4130

  Rosen, Hugo R ^a  

^a UNIVERSITY OF COLORADO   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BOCEPREVIR; CELL SURFACE PROTEIN; DOUBLE STRANDED RNA; INTERFERON REGULATORY FACTOR 3; INTERFERON REGULATORY FACTOR 7; INTERLEUKIN 1 RECEPTOR; INTERLEUKIN 10; INTERLEUKIN 10 RECEPTOR BETA; INTERLEUKIN 28A; MESSENGER RNA; MYELOID DIFFERENTIATION FACTOR 88; NATURAL CYTOTOXICITY TRIGGERING RECEPTOR 1; NATURAL CYTOTOXICITY TRIGGERING RECEPTOR 3; NATURAL KILLER CELL RECEPTOR NKG2A; PATTERN RECOGNITION RECEPTOR; PROGRAMMED DEATH 1 LIGAND 1; PROTEIN KINASE R; RETINOIC ACID INDUCIBLE PROTEIN I; STAT1 PROTEIN; TELAPREVIR; TOLL LIKE RECEPTOR 2; TOLL LIKE RECEPTOR 3; TOLL LIKE RECEPTOR 7; TUMOR NECROSIS FACTOR RECEPTOR ASSOCIATED FACTOR 3; TUMOR NECROSIS FACTOR RELATED APOPTOSIS INDUCING LIGAND;

ADAPTIVE IMMUNITY; ANTIPROLIFERATIVE ACTIVITY; ANTIVIRAL THERAPY; ARTICLE; CELL PROLIFERATION; CELL SURFACE; CYTOKINE PRODUCTION; DISEASE COURSE; DNA RESPONSIVE ELEMENT; ENDOCYTOSIS; GENETIC ASSOCIATION; GENETIC VARIABILITY; GENOTYPE; HEPATITIS C; HEPATITIS C VIRUS; HUMAN; IMMUNE EVASION; IMMUNORECEPTOR TYROSINE BASED INHIBITION MOTIF; INNATE IMMUNITY; INTERNAL RIBOSOME ENTRY SITE; LIVER BIOPSY; LIVER TRANSPLANTATION; MICROENVIRONMENT; NONHUMAN; OUTCOME ASSESSMENT; POINT MUTATION; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; RNA REPLICATION; STELLATE CELL; TRANSCYTOSIS; VIRAL CLEARANCE; VIRUS ENTRY; VIRUS REPLICATION;

ADAPTIVE IMMUNITY; ANIMALS; HEPACIVIRUS; HEPATITIS C; HEPATOCYTES; HOST-PATHOGEN INTERACTIONS; HUMANS; IMMUNE EVASION; IMMUNITY, INNATE; T-LYMPHOCYTES, CYTOTOXIC; VIRUS REPLICATION;

EID: 84885060120     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI67714     Document Type: Article

References (151)

1. Rosen HR. Clinical practice. Chronic hepatitis C infection. N Engl J Med. 2011;364(25):2429-2438.
2. Mitchell AE, Colvin HM, Palmer Beasley R. Institute of Medicine recommendations for the prevention and control of hepatitis B and C. Hepatology. 2010;51(3):729-733.
3. Davis GL, Albright JE, Cook SF, Rosenberg DM. Projecting future complications of chronic hepatitis C in the United States. Liver Transpl. 2003;9(4):331-338.
4. Biggins SW, et al. Projected future increase in aging hepatitis C virus-infected liver transplant candidates: a potential effect of hepatocellular carcinoma. Liver Transpl. 2012;18(12):1471-1478.
5. Aronsohn A, Jensen D. Distributive justice and the arrival of direct-acting antivirals: who should be first in line? Hepatology. 2011;53(6):1789-1791.
6. Dabbouseh NM, Jensen DM. Future therapies for chronic hepatitis C. Nat Rev Gastroenterol Hepatol. 2013;10(5):268-276.
7. Gane EJ, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med. 2013;368(1):34-44.
8. Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science. 1989;244(4902):359-362.
9. Rice CM. New insights into HCV replication: potential antiviral targets. Top Antivir Med. 2011;19(3):117-120.
10. Rehermann B. Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence. J Clin Invest. 2009;119(7):1745-1754.
11. Bartenschlager R, Pietschmann T. Efficient hepatitis C virus cell culture system: what a difference the host cell makes. Proc Natl Acad Sci U S A. 2005;102(28):9739-9740.
12. Li K, et al. Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. Proc Natl Acad Sci U S A. 2005;102(8):2992-2997.
13. Wakita T, et al. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med. 2005;11(7):791-796.
14. Zhong J, et al. Robust hepatitis C virus infection in vitro. Proc Natl Acad Sci U S A. 2005;102(26):9294-9299.
15. Lindenbach BD, et al. Complete replication of hepatitis C virus in cell culture. Science. 2005;309(5734):623-626.
16. Arnaud N, et al. Hepatitis C virus reveals a novel early control in acute immune response. PLoS Pathog. 2011;7(10):e1002289.
17. Kim MJ, Hwang SY, Imaizumi T, Yoo JY. Negative feedback regulation of RIG-I-mediated antiviral signaling by interferon-induced ISG15 conjugation. J Virol. 2008;82(3):1474-1483.
18. Arnaud N, et al. Hepatitis C virus controls interferon production through PKR activation. PLoS One. 2010;5(5):e10575.
19. Horner SM, Gale M. Intracellular innate immune cascades and interferon defenses that control hepatitis C virus. J Interferon Cytokine Res. 2009;29(9):489-498.
20. Saito T, Owen DM, Jiang F, Marcotrigiano J, Gale M. Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA. Nature. 2008;454(7203):523-527.
21. Horner SM, Liu HM, Park HS, Briley J, Gale M. Mitochondrial-associated endoplasmic reticulum membranes (MAM) form innate immune synapses and are targeted by hepatitis C virus. Proc Natl Acad Sci U S A. 2011;108(35):14590- 14595.
22. Zhou Z, Hamming OJ, Ank N, Paludan SR, Nielsen AL, Hartmann R. Type III interferon (IFN) induces a type I IFN-like response in a restricted subset of cells through signaling pathways involving both the Jak-STAT pathway and the mitogen-activated protein kinases. J Virol. 2007;81(14):7749-7758.
23. Choubey D, Moudgil KD. Interferons in autoimmune and inflammatory diseases: regulation and roles. J Interferon Cytokine Res. 2011;31(12):857-865.
24. Balagopal A, Thomas DL, Thio CL. IL28B and the control of hepatitis C virus infection. Gastroenterology. 2010;139(6):1865-1876.
25. Thomas E, et al. HCV infection induces a unique hepatic innate immune response associated with robust production of type III interferons. Gastroenterology. 2012;142(4):978-988.
26. Park H, et al. IL-29 is the dominant type III interferon produced by hepatocytes during acute hepatitis C virus infection. Hepatology. 2012;56(6):2060-2070.
27. Helbig KJ, et al. The antiviral protein viperin inhibits hepatitis C virus replication via interaction with nonstructural protein 5A. Hepatology. 2011;54(5):1506-1517.
28. Raychoudhuri A, Shrivastava S, Steele R, Kim H, Ray R, Ray RB. ISG56 and IFITM1 proteins inhibit hepatitis C virus replication. J Virol. 2011;85(24):12881-12889.
29. Osterlund PI, Pietila TE, Veckman V, Kotenko SV, Julkunen I. IFN regulatory factor family members differentially regulate the expression of type III IFN (IFNlambda) genes. J Immunol. 2007;179(6):3434-3442.
30. Yamane D, McGivern DR, Masaki T, Lemon SM. Liver injury and disease pathogenesis in chronic hepatitis C. Curr Top Microbiol Immunol. 2013;369:263-288.
31. Mengshol JA, Golden-Mason L, Rosen HR. Mechanisms of disease: HCV-induced liver injury. Nat Clin Pract Gastroenterol Hepatol. 2007;4(11):622-634.
32. Randall G, et al. Silencing of USP18 potentiates the antiviral activity of interferon against hepatitis C virus infection. Gastroenterology. 2006;131(5):1584-1591.
33. Sarasin-Filipowicz M, et al. Alpha interferon induces long-lasting refractoriness of JAKSTAT signaling in the mouse liver through induction of USP18/UBP43. Mol Cell Biol. 2009;29(17):4841-4851.
34. Afdhal NH, et al. Hepatitis C pharmacogenetics: state of the art in 2010. Hepatology. 2011;53(1):336-345.
35. Ge D, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009;461(7262):399-401.
36. Thomas DL, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature. 2009;461(7265):798-801.
37. Marcello T, et al. Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics. Gastroenterology. 2006;131(6):1887-1898.
38. Thompson AJ, et al. Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology. 2010;139(1):120-129. e18.
39. Urban TJ, et al. IL28B genotype is associated with differential expression of intrahepatic interferonstimulated genes in patients with chronic hepatitis C. Hepatology. 2010;52(6):1888-1896.
40. Sarasin-Filipowicz M, et al. Interferon signaling and treatment outcome in chronic hepatitis C. Proc Natl Acad Sci U S A. 2008;105(19):7034-7039.
41. Beinhardt S, et al. Serum level of IP-10 increases predictive value of IL28B polymorphisms for spontaneous clearance of acute HCV infection. Gastroenterology. 2012;142(1):78-85. e2.
42. Casrouge A, et al. Evidence for an antagonist form of the chemokine CXCL10 in patients chronically infected with HCV. J Clin Invest. 2011;121(1):308-317.
43. Darling JM, et al. Quantitation of pretreatment serum interferon-gamma-inducible protein-10 improves the predictive value of an IL28B gene polymorphism for hepatitis C treatment response. Hepatology. 2011;53(1):14-22.
44. Prokunina-Olsson L, et al. A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat Genet. 2013;45(2):164-171.
45. Lande R, Gilliet M. Plasmacytoid dendritic cells: key players in the initiation and regulation of immune responses. Ann N Y Acad Sci. 2010;1183:89-103.
46. Hagberg N, et al. IFN-alpha production by plasmacytoid dendritic cells stimulated with RNAcontaining immune complexes is promoted by NK cells via MIP-1beta and LFA-1. J Immunol. 2011;186(9):5085-5094.
47. Takahashi K, et al. Plasmacytoid dendritic cells sense hepatitis C virus-infected cells, produce interferon, and inhibit infection. Proc Natl Acad Sci U S A. 2010;107(16):7431-7436.
48. Dreux M, et al. Short-range exosomal transfer of viral RNA from infected cells to plasmacytoid dendritic cells triggers innate immunity. Cell Host Microbe. 2012;12(4):558-570.
49. Stone AE, et al. Hepatitis C virus pathogen associated molecular pattern (PAMP) triggers production of lambda-interferons by human plasmacytoid dendritic cells. PLoS Pathog. 2013;9(4):e1003316.
50. Takeuchi O, Akira S. MDA5/RIG-I and virus recognition. Curr Opin Immunol. 2008;20(1):17-22.
51. Sagan SM, Sarnow P. Plasmacytoid dendritic cells as guardians in hepatitis C virus-infected liver. Proc Natl Acad Sci U S A. 2010;107(17):7625- 7626.
52. Wertheimer AM, Bakke A, Rosen HR. Direct enumeration and functional assessment of circulating dendritic cells in patients with liver disease. Hepatology. 2004;40(2):335-345.
53. Liang H, et al. Differential effects of hepatitis C virus JFH1 on human myeloid and plasmacytoid dendritic cells. J Virol. 2009;83(11):5693-5707.
54. Shiina M, Rehermann B. Cell culture-produced hepatitis C virus impairs plasmacytoid dendritic cell function. Hepatology. 2008;47(2):385-395.
55. Florentin J, et al. HCV glycoprotein E2 is a novel BDCA-2 ligand and acts as an inhibitor of IFN production by plasmacytoid dendritic cells. Blood. 2012;120(23):4544-4551.
56. Yoshio S, et al. Human blood dendritic cell antigen 3 (BDCA3) dendritic cells are a potent producer of interferon-lambda in response to hepatitis C virus. Hepatology. 2013;57(5):1705-1715.
57. Honda M, et al. Hepatic ISG expression is associated with genetic variation in interleukin 28B and the outcome of IFN therapy for chronic hepatitis C. Gastroenterology. 2010;139(2):499-509.
58. Biggins SW, et al. Differential effects of donor and recipient IL28B and DDX58 SNPs on severity of HCV after liver transplantation. J Hepatol. 2013;58(5):969-976.
59. Biron CA. Initial and innate responses to viral infections-pattern setting in immunity or disease. Curr Opin Microbiol. 1999;2(4):374-381.
60. Vivier E, et al. Innate or adaptive immunity? The example of natural killer cells. Science. 2011;331(6013):44-49.
61. Jost S, Altfeld M. Control of human viral infections by natural killer cells. Annu Rev Immunol. 2013;31:163-194.
62. Biron CA, Brossay L. NK cells and NKT cells in innate defense against viral infections. Curr Opin Immunol. 2001;13(4):458-464.
63. Cooper MA, Fehniger TA, Caligiuri MA. The biology of human natural killer-cell subsets. Trends Immunol. 2001;22(11):633-640.
64. Paust S, et al. Critical role for the chemokine receptor CXCR6 in NK cell-mediated antigen-specific memory of haptens and viruses. Nat Immunol. 2010;11(12):1127-1135.
65. Jiang X, Chen Y, Peng H, Tian Z. Memory NK cells: why do they reside in the liver? Cell Mol Immunol. 2013;10(3):196-201.
66. Moretta A, et al. Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol. 2001;19:197-223.
67. Lanier LL. NK cell recognition. Annu Rev Immunol. 2005;23:225-274.
68. Moretta A, Biassoni R, Bottino C, Mingari MC, Moretta L. Natural cytotoxicity receptors that trigger human NK-cell-mediated cytolysis. Immunol Today. 2000;21(5):228-234.
69. De Maria A, Bozzano F, Cantoni C, Moretta L. Revisiting human natural killer cell subset function revealed cytolytic CD56 (dim) CD16+ NK cells as rapid producers of abundant IFN-β on activation. Proc Natl Acad Sci U S A. 2011;108(2):728-732.
70. Golden-Mason L, Cox AL, Randall JA, Cheng L, Rosen HR. Increased natural killer cell cytotoxicity and NKp30 expression protects against hepatitis C virus infection in high-risk individuals and inhibits replication in vitro. Hepatology. 2010;52(5):1581-1589.
71. Golden-Mason L, Rosen HR. Natural killer cells: primary target for hepatitis C virus immune evasion strategies? Liver Transpl. 2006;12(3):363-372.
72. Sivori S, et al. NKp46 is the major triggering receptor involved in the natural cytotoxicity of fresh or cultured human NK cells. Correlation between surface density of NKp46 and natural cytotoxicity against autologous, allogeneic or xenogeneic target cells. Eur J Immunol. 1999;29(5):1656-1666.
73. Mandelboim O, et al. Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells. Nature. 2001;409(6823):1055- 1060.
74. Thomas DL, et al. The natural history of hepatitis C virus infection: host, viral, and environmental factors. JAMA. 2000;284(4):450-456.
75. Rosen HR, et al. Selective decrease in hepatitis C virus-specific immunity among African Americans and outcome of antiviral therapy. Hepatology. 2007;46(2):350-358.
76. Golden-Mason L, Stone AE, Bambha KM, Cheng L, Rosen HR. Race- and gender-related variation in NKp46 expression associated with differential anti-HCV immunity. Hepatology. 2012;56(4):1214-1222.
77. Kramer B, et al. Natural killer p46High expression defines a natural killer cell subset that is potentially involved in control of hepatitis C virus replication and modulation of liver fibrosis. Hepatology. 2012;56(4):1201-1213.
78. Heeg M, Thimme R. NK cells and hepatitis C: NKp46 expression linked to antiviral and antifibrotic activity. Hepatology. 2012;56(4):1197-1200.
79. Gonzalez VD, et al. Expansion of functionally skewed CD56-negative NK cells in chronic hepatitis C virus infection: correlation with outcome of pegylated IFN-alpha and ribavirin treatment. J Immunol. 2009;183(10):6612-6618.
80. Golden-Mason L, et al. Natural killer inhibitory receptor expression associated with treatment failure and interleukin-28B genotype in patients with chronic hepatitis C. Hepatology. 2011;54(5):1559-1569.
81. Lan L, et al. Hepatitis C virus infection sensitizes human hepatocytes to TRAIL-induced apoptosis in a caspase 9-dependent manner. J Immunol. 2008;181(7):4926-4935.
82. Stegmann KA, et al. Interferon-alpha-induced TRAIL on natural killer cells is associated with control of hepatitis C virus infection. Gastroenterology. 2010;138(5):1885-1897.
83. Ahlenstiel G, et al. Early changes in natural killer cell function indicate virologic response to interferon therapy for hepatitis C. Gastroenterology. 2011;141(4):1231-1239.
84. Edlich B, et al. Early changes in interferon signaling define natural killer cell response and refractoriness to interferon-based therapy of hepatitis C patients. Hepatology. 2012;55(1):39-48.
85. Vollmar B, Menger MD. The hepatic microcirculation: mechanistic contributions and therapeutic targets in liver injury and repair. Physiol Rev. 2009;89(4):1269-1339.
86. Chen L, et al. Cell-type specific gene expression signature in liver underlies response to interferon therapy in chronic hepatitis C infection. Gastroenterology. 2010;138(3):1123-1123.
87. Negash AA, et al. IL-1beta production through the NLRP3 inflammasome by hepatic macrophages links hepatitis C virus infection with liver inflammation and disease. PLoS Pathog. 2013;9(4):e1003330.
88. Dolganiuc A, et al. Viral and host factors induce macrophage activation and loss of toll-like receptor tolerance in chronic HCV infection. Gastroenterology. 2007;133(5):1627-1636.
89. Tu Z, Pierce RH, Kurtis J, Kuroki Y, Crispe IN, Orloff MS. Hepatitis C virus core protein subverts the antiviral activities of human Kupffer cells. Gastroenterology. 2010;138(1):305-314.
90. Sen GC, Sarkar SN. Transcriptional signaling by double-stranded RNA: role of TLR3. Cytokine Growth Factor Rev. 2005;16(1):1-14.
91. 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(17):9249-9258.
92. Kassel R, Cruise MW, Iezzoni JC, Taylor NA, Pruett TL, Hahn YS. Chronically inflamed livers up-regulate expression of inhibitory B7 family members. Hepatology. 2009;50(5):1625-1637.
93. Anderson AC, et al. Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells. Science. 2007;318(5853):1141- 1143.
94. Mengshol JA, et al. A crucial role for Kupffer cell-derived galectin-9 in regulation of T cell immunity in hepatitis C infection. PLoS One. 2010;5(3):e9504.
95. Li H, et al. Tim-3/galectin-9 signaling pathway mediates T cell dysfunction and predicts poor prognosis in patients with HBV-associated hepatocellular carcinoma. Hepatology. 2012;56(4):1342-1351.
96. Golden-Mason L, et al. Galectin-9 functionally impairs natural killer (NK) cells in humans and mice. J Virol. 2013;87(9):4835-4845.
97. Seternes T, Sorensen K, Smedsrod B. Scavenger endothelial cells of vertebrates: a nonperipheral leukocyte system for high-capacity elimination of waste macromolecules. Proc Natl Acad Sci U S A. 2002;99(11):7594-7597.
98. Karrar A, Broome U, Uzunel M, Qureshi AR, Sumitran-Holgersson S. Human liver sinusoidal endothelial cells induce apoptosis in activated T cells: a role in tolerance induction. Gut. 2007;56(2):243-252.
99. Tiegs G, Lohse AW. Immune tolerance: what is unique about the liver. J Autoimmun. 2010;34(1):1-6.
100. Wu J, et al. Toll-like receptor-induced innate immune responses in non-parenchymal liver cells are cell type-specific. Immunology. 2010;129(3):363-374.
101. Huebert RC, et al. Immortalized liver endothelial cells: a cell culture model for studies of motility and angiogenesis. Lab Invest. 2010;90(12):1770- 1781.
102. Cormier EG, et al. L-SIGN (CD209L) and DCSIGN (CD209) mediate transinfection of liver cells by hepatitis C virus. Proc Natl Acad Sci U S A. 2004;101(39):14067-14072.
103. Ganesan LP, Mohanty S, Kim J, Clark KR, Robinson JM, Anderson CL. Rapid and efficient clearance of blood-borne virus by liver sinusoidal endothelium. PLoS Pathog. 2011;7(9):e1002281.
104. Li J, et al. Exosomes mediate the cell-to-cell transmission of IFN-á-induced antiviral activity. Nat Immunol. 2013;14(8):793-803.
105. Rehermann B. Cellular immune response to the hepatitis C virus. J Viral Hepat. 1999;6(suppl 1):31-35.
106. Liu L, Fisher BE, Dowd KA, Astemborski J, Cox AL, Ray SC. Acceleration of hepatitis C virus envelope evolution in humans is consistent with progressive humoral immune selection during the transition from acute to chronic infection. J Virol. 2010;84(10):5067-5077.
107. Christie JM, et al. Clinical outcome of hypogammaglobulinaemic patients following outbreak of acute hepatitis C:2 year follow up. Clin Exp Immunol. 1997;110(1):4-8.
108. Pestka JM, et al. Rapid induction of virus-neutralizing antibodies and viral clearance in a single-source outbreak of hepatitis C. Proc Natl Acad Sci U S A. 2007;104(14):6025-6030.
109. Bartosch B, et al. An interplay between hypervariable region 1 of the hepatitis C virus E2 glycoprotein, the scavenger receptor BI, and high-density lipoprotein promotes both enhancement of infection and protection against neutralizing antibodies. J Virol. 2005;79(13):8217-8229.
110. Lai ME, et al. Hepatitis C virus in multiple episodes of acute hepatitis in polytransfused thalassaemic children. Lancet. 1994;343(8894):388-390.
111. Bukh J. Animal models for the study of hepatitis C virus infection and related liver disease. Gastroenterology. 2012;142(6):1279-1287. e3.
112. Lacek K, et al. Novel human SR-BI antibodies prevent infection and dissemination of HCV in vitro and in humanized mice. J Hepatol. 2012;57(1):17-23.
113. Jo J, et al. Analysis of CD8+ T-cell-mediated inhibition of hepatitis C virus replication using a novel immunological model. Gastroenterology. 2009;136(4):1391-1401.
114. Lechner F, et al. Analysis of successful immune responses in persons infected with hepatitis C virus. J Exp Med. 2000;191(9):1499-1512.
115. Smyk-Pearson S, Tester IA, Lezotte D, Sasaki AW, Lewinsohn DM, Rosen HR. Differential antigenic hierarchy associated with spontaneous recovery from hepatitis C virus infection: implications for vaccine design. J Infect Dis. 2006;194(4):454-463.
116. Tester I, et al. Immune evasion versus recovery after acute hepatitis C virus infection from a shared source. J Exp Med. 2005;201(11):1725-1731.
117. Bowen DG, Walker CM. Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature. 2005;436(7053):946-952.
118. Bowen DG, Walker CM. Mutational escape from CD8+ T cell immunity: HCV evolution, from chimpanzees to man. J Exp Med. 2005;201(11):1709-1714.
119. Grakoui A, et al. HCV persistence and immune evasion in the absence of memory T cell help. Science. 2003;302(5645):659-662.
120. Smyk-Pearson S, et al. Spontaneous recovery in acute human hepatitis C virus infection: functional T-cell thresholds and relative importance of CD4 help. J Virol. 2008;82(4):1827-1837.
121. Oniangue-Ndza C, et al. Compensatory mutations restore the replication defects caused by cytotoxic T lymphocyte escape mutations in hepatitis C virus polymerase. J Virol. 2011;85(22):11883-11890.
122. Neumann-Haefelin C, et al. Human leukocyte antigen B27 selects for rare escape mutations that significantly impair hepatitis C virus replication and require compensatory mutations. Hepatology. 2011;54(4):1157-1166.
123. Fitzmaurice K, et al. Molecular footprints reveal the impact of the protective HLA-A 03 allele in hepatitis C virus infection. Gut. 2011;60(11):1563-1571.
124. Virgin HW, Wherry EJ, Ahmed R. Redefining chronic viral infection. Cell. 2009;138(1):30-50.
125. Rosen HR. Transplantation immunology: what the clinician needs to know for immunotherapy. Gastroenterology. 2008;134(6):1789-1801.
126. Radziewicz H, 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(6):2545-2553.
127. Golden-Mason L, Klarquist J, Wahed AS, Rosen HR. Cutting edge: programmed death-1 expression is increased on immunocytes in chronic hepatitis C virus and predicts failure of response to antiviral therapy: race-dependent differences. J Immunol. 2008;180(6):3637-3641.
128. Seigel B, Bengsch B, Lohmann V, Bartenschlager R, Blum HE, Thimme R. Factors that determine the antiviral efficacy of HCV-specific CD8 (+) T cells ex vivo. Gastroenterology. 2013;144(2):426-436.
129. Bengsch B, et al. 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(6):e1000947.
130. Wood NA, Linn ML, Bowen DG. Exhausted or just sleeping: awakening virus-specific responses in chronic hepatitis C virus infection. Hepatology. 2011;54(5):1879-1882.
131. McMahan RH, et al. Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocytedirected in vitro cytotoxicity. J Clin Invest. 2010;120(12):4546-4557.
132. Snyder JT, Alexander-Miller MA, Berzofskyl JA, Belyakov IM. Molecular mechanisms and biological significance of CTL avidity. Curr HIV Res. 2003;1(3):287-294.
133. Slifka MK, Whitton JL. Functional avidity maturation of CD8 (+) T cells without selection of higher affinity TCR. Nat Immunol. 2001;2(8):711-717.
134. Sedlik C, et al. In vivo induction of a high-avidity, high-frequency cytotoxic T-lymphocyte response is associated with antiviral protective immunity. J Virol. 2000;74(13):5769-5775.
135. Lee JK, et al. T cell cross-reactivity and conformational changes during TCR engagement. J Exp Med. 2004;200(11):1455-1466.
136. Yerly D, et al. Increased cytotoxic T-lymphocyte epitope variant cross-recognition and functional avidity are associated with hepatitis C virus clearance. J Virol. 2008;82(6):3147-3153.
137. Dazert E, et al. 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(2):376-386.
138. Zhang Y, et al. Transduction of human T cells with a novel T-cell receptor confers anti-HCV reactivity. PLoS Pathog. 2010;6(7):e1001018.
139. Pasetto A, et al. TCR-redirected human T cells inhibit hepatitis C virus replication: hepatotoxic potential is linked to antigen specificity and functional avidity. J Immunol. 2012;189(9):4510-4519.
140. Houghton M. Prospects for prophylactic and therapeutic vaccines against the hepatitis C viruses. Immunol Rev. 2011;239(1):99-108.
141. Gottwein JM, et al. Development and characterization of hepatitis C virus genotype 1-7 cell culture systems: role of CD81 and scavenger receptor class B type I and effect of antiviral drugs. Hepatology. 2009;49(2):364-377.
142. Folgori A, et al. A T-cell HCV vaccine eliciting effective immunity against heterologous virus challenge in chimpanzees. Nat Med. 2006;12(2):190-197.
143. Zubkova I, et al. T-cell vaccines that elicit effective immune responses against HCV in chimpanzees may create greater immune pressure for viral mutation. Vaccine. 2009;27(19):2594-2602.
144. Feinstone SM, Hu DJ, Major ME. Prospects for prophylactic and therapeutic vaccines against hepatitis C virus. Clin Infect Dis. 2012;55(suppl 1):S25-S32.
145. Rollier CS, et al. Vaccine-induced early control of hepatitis C virus infection in chimpanzees fails to impact on hepatic PD-1 and chronicity. Hepatology. 2007;45(3):602-613.
146. Burton JR, et al. Prospective analysis of effector and regulatory CD4+ T cells in chronic HCV patients undergoing combination antiviral therapy. J Hepatol. 2008;49(3):329-338.
147. Gale M, Foy EM. Evasion of intracellular host defence by hepatitis C virus. Nature. 2005;436(7053):939-945.
148. Golden-Mason L, et al. Loss of IL-7 receptor á-chain (CD127) expression in acute HCV infection associated with viral persistence. Hepatology. 2006;44(5):1098-1109.
149. Shin EC, et al. The frequency of CD127 (+) hepatitis C virus (HCV)-specific T cells but not the expression of exhaustion markers predicts the outcome of acute HCV infection. J Virol. 2013;87(8):4772-4777.
150. Tacke RS, et al. Myeloid suppressor cells induced by hepatitis C virus suppress T-cell responses through the production of reactive oxygen species. Hepatology. 2012;55(2):343-353.
151. Radziewicz H, Dunham RM, Grakoui A. PD-1 tempers Tregs in chronic HCV infection. J Clin Invest. 2009;119(3):450-453.