The role of innate immunity in the immunopathology and treatment of HBV infection

Journal of Hepatology

Volumn 64, Issue 1, 2016, Pages S60-S70

  Maini, Mala K ^a   Gehring, Adam J ^b  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

^b SAINT LOUIS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

HBV innate immunity; Innate immunotherapy; Innate sensors; Interferon alpha; MAITs; MDSC; Monocytes; NK cells

Indexed keywords

ALPHA INTERFERON; CYTOKINE; INTERFERON; TOLL LIKE RECEPTOR AGONIST; ANTIVIRUS AGENT; HEPATITIS B ANTIBODY;

ADAPTIVE IMMUNITY; BYSTANDER EFFECT; EFFECTOR CELL; HEPATITIS B; HUMAN; IMMUNOLOGICAL TOLERANCE; IMMUNOPATHOLOGY; IMMUNOREGULATION; INFECTION CONTROL; INNATE IMMUNITY; KUPFFER CELL; MONOCYTE; MYELOID-DERIVED SUPPRESSOR CELL; NATURAL KILLER CELL; NONHUMAN; PRIORITY JOURNAL; REVIEW; T LYMPHOCYTE; VIRUS DETECTION; VIRUS PATHOGENESIS; CHRONIC HEPATITIS B; HEPATITIS B VIRUS; HOST PATHOGEN INTERACTION; IMMUNE EVASION; IMMUNOLOGY; PATHOLOGY; SIGNAL TRANSDUCTION; VIROLOGY;

ANTIVIRAL AGENTS; HEPATITIS B ANTIBODIES; HEPATITIS B VIRUS; HEPATITIS B, CHRONIC; HOST-PATHOGEN INTERACTIONS; HUMANS; IMMUNE EVASION; IMMUNITY, INNATE; SIGNAL TRANSDUCTION; T-LYMPHOCYTES;

EID: 84983619763     PISSN: 01688278     EISSN: 16000641     Source Type: Journal    
DOI: 10.1016/j.jhep.2016.01.028     Document Type: Review

References (121)

1. [1] Gold, M.C., McLaren, J.E., Reistetter, J.A., Smyk-Pearson, S., Ladell, K., Swarbrick, G.M., et al. MR1-restricted MAIT cells display ligand discrimination and pathogen selectivity through distinct T cell receptor usage. J Exp Med 211 (2014), 1601–1610.
2. [2] Sun, J.C., Beilke, J.N., Lanier, L.L., Adaptive immune features of natural killer cells. Nature 457 (2009), 557–561.
3. [3] Vivier, E., Raulet, D.H., Moretta, A., Caligiuri, M.A., Zitvogel, L., Lanier, L.L., et al. Innate or adaptive immunity? The example of natural killer cells. Science 331 (2011), 44–49.
4. [4] Doherty, D.G., Norris, S., Madrigal-Estebas, L., McEntee, G., Traynor, O., Hegarty, J.E., et al. The human liver contains multiple populations of NK cells, T cells, and CD3+CD56+ natural T cells with distinct cytotoxic activities and Th1, Th2, and Th0 cytokine secretion patterns. J Immunol 163 (1999), 2314–2321.
5. [5] Dunn, C., Brunetto, M., Reynolds, G., Christophides, T., Kennedy, P.T., Lampertico, P., et al. Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage. J Exp Med 204 (2007), 667–680.
6. [6] Hammerich, L., Tacke, F., Emerging roles of myeloid derived suppressor cells in hepatic inflammation and fibrosis. World J Gastrointest Pathophysiol 6 (2015), 43–50.
7. [7] Jo, J., Tan, A.T., Ussher, J.E., Sandalova, E., Tang, X.Z., Tan-Garcia, A., et al. Toll-like receptor 8 agonist and bacteria trigger potent activation of innate immune cells in human liver. PLoS Pathog, 10, 2014, e1004210.
8. [8] Lepore, M., Kalinichenko, A., Colone, A., Paleja, B., Singhal, A., Tschumi, A., et al. Parallel T-cell cloning and deep sequencing of human MAIT cells reveal stable oligoclonal TCRbeta repertoire. Nat Commun, 5, 2014, 3866.
9. [9] McHedlidze, T., Waldner, M., Zopf, S., Walker, J., Rankin, A.L., Schuchmann, M., et al. Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis. Immunity 39 (2013), 357–371.
10. [10] Crispe, I.N., Immune tolerance in liver disease. Hepatology 60 (2014), 2109–2117.
11. [11] Nath, B., Szabo, G., Hypoxia and hypoxia inducible factors: diverse roles in liver diseases. Hepatology 55 (2012), 622–633.
12. [12] Protzer, U., Maini, M.K., Knolle, P.A., Living in the liver: hepatic infections. Nat Rev Immunol 12 (2012), 201–213.
13. [13] Cooper, A., Tal, G., Lider, O., Shaul, Y., Cytokine induction by the hepatitis B virus capsid in macrophages is facilitated by membrane heparan sulfate and involves TLR2. J Immunol 175 (2005), 3165–3176.
14. [14] Li, M., Sun, R., Xu, L., Yin, W., Chen, Y., Zheng, X., et al. Kupffer cells support hepatitis B virus-mediated CD8+ T cell exhaustion via hepatitis B core antigen-TLR2 interactions in mice. J Immunol 195 (2015), 3100–3109.
15. [15] Vanlandschoot, P., Van Houtte, F., Hoek, F., Nieuwland, R., Leroux-Roels, G., Saccharomyces cerevisiae-derived HBsAg preparations differ in their attachment to monocytes, immune-suppressive potential, and T-cell immunogenicity. J Med Virol 70 (2003), 513–519.
16. [16] Vanlandschoot, P., Van Houtte, F., Roobrouck, A., Farhoudi, A., Stelter, F., Peterson, D.L., et al. LPS-binding protein and CD14-dependent attachment of hepatitis B surface antigen to monocytes is determined by the phospholipid moiety of the particles. J Gen Virol 83 (2002), 2279–2289.
17. [17] Sato, S., Li, K., Kameyama, T., Hayashi, T., Ishida, Y., Murakami, S., et al. The RNA sensor RIG-I dually functions as an innate sensor and direct antiviral factor for hepatitis B virus. Immunity 42 (2015), 123–132.
18. [18] Cui, X., Clark, D.N., Liu, K., Xu, X.D., Guo, J.T., Hu, J., Viral DNA-dependent induction of innate immune response to hepatitis B virus in immortalized mouse hepatocytes. J Virol 90 (2015), 486–496.
19. [19] Zlotnick, A., Ceres, P., Singh, S., Johnson, J.M., A small molecule inhibits and misdirects assembly of hepatitis B virus capsids. J Virol 76 (2002), 4848–4854.
20. [20] Cai, C.W., Lomonosova, E., Moran, E.A., Cheng, X., Patel, K.B., Bailly, F., et al. Hepatitis B virus replication is blocked by a 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) inhibitor of the viral ribonuclease H activity. Antiviral Res 108 (2014), 48–55.
21. [21] Hu, Y., Cheng, X., Cao, F., Huang, A., Tavis, J.E., Beta-Thujaplicinol inhibits hepatitis B virus replication by blocking the viral ribonuclease H activity. Antiviral Res 99 (2013), 221–229.
22. [22] Lu, G., Lomonosova, E., Cheng, X., Moran, E.A., Meyers, M.J., Le Grice, S.F., et al. Hydroxylated tropolones inhibit hepatitis B virus replication by blocking viral ribonuclease H activity. Antimicrob Agents Chemother 59 (2015), 1070–1079.
23. [23] Bertoletti, A., Ferrari, C., Innate and adaptive immune responses in chronic hepatitis B virus infections: towards restoration of immune control of viral infection. Gut 61 (2012), 1754–1764.
24. [24] Lucifora, J., Durantel, D., Testoni, B., Hantz, O., Levrero, M., Zoulim, F., Control of hepatitis B virus replication by innate response of HepaRG cells. Hepatology 51 (2010), 63–72.
25. [25] Shlomai, A., Schwartz, R.E., Ramanan, V., Bhatta, A., de Jong, Y.P., Bhatia, S.N., et al. Modeling host interactions with hepatitis B virus using primary and induced pluripotent stem cell-derived hepatocellular systems. Proc Natl Acad Sci USA 111 (2014), 12193–12198.
26. [26] Luangsay, S., Gruffaz, M., Isorce, N., Testoni, B., Michelet, M., Faure-Dupuy, S., et al. Early inhibition of hepatocyte innate responses by hepatitis B virus. J Hepatol 63 (2015), 1314–1322.
27. [27] Wu, J., Meng, Z., Jiang, M., Pei, R., Trippler, M., Broering, R., et al. Hepatitis B virus suppresses toll-like receptor-mediated innate immune responses in murine parenchymal and nonparenchymal liver cells. Hepatology 49 (2009), 1132–1140.
28. [28] Lutgehetmann, M., Bornscheuer, T., Volz, T., Allweiss, L., Bockmann, J.H., Pollok, J.M., et al. Hepatitis B virus limits response of human hepatocytes to interferon-alpha in chimeric mice. Gastroenterology 140 (2011), 2074–2083 [2083 e2071–2072].
29. [29] Dunn, C., Peppa, D., Khanna, P., Nebbia, G., Jones, M., Brendish, N., et al. Temporal analysis of early immune responses in patients with acute hepatitis B virus infection. Gastroenterology 137 (2009), 1289–1300.
30. [30] Stacey, A.R., Norris, P.J., Qin, L., Haygreen, E.A., Taylor, E., Heitman, J., et al. Induction of a striking systemic cytokine cascade prior to peak viremia in acute human immunodeficiency virus type 1 infection, in contrast to more modest and delayed responses in acute hepatitis B and C virus infections. J Virol 83 (2009), 3719–3733.
31. [31] Wieland, S., Thimme, R., Purcell, R.H., Chisari, F.V., Genomic analysis of the host response to hepatitis B virus infection. Proc Natl Acad Sci USA 101 (2004), 6669–6674.
32. [32] Das, A., Ellis, G., Pallant, C., Lopes, A.R., Khanna, P., Peppa, D., et al. IL-10-producing regulatory B cells in the pathogenesis of chronic hepatitis B virus infection. J Immunol 189 (2012), 3925–3935.
33. [33] Heymann, F., Peusquens, J., Ludwig-Portugall, I., Kohlhepp, M., Ergen, C., Niemietz, P., et al. Liver inflammation abrogates immunological tolerance induced by Kupffer cells. Hepatology 62 (2015), 279–291.
34. [34] Chang, J.J., Thompson, A.J., Visvanathan, K., Kent, S.J., Cameron, P.U., Wightman, F., et al. The phenotype of hepatitis B virus-specific T cells differ in the liver and blood in chronic hepatitis B virus infection. Hepatology 46 (2007), 1332–1340.
35. [35] Vanwolleghem, T., Hou, J., van Oord, G., Andeweg, A.C., Osterhaus, A.D., Pas, S.D., et al. Re-evaluation of hepatitis B virus clinical phases by systems biology identifies unappreciated roles for the innate immune response and B cells. Hepatology 62 (2015), 87–100.
36. [36] Hong, M., Sandalova, E., Low, D., Gehring, A.J., Fieni, S., Amadei, B., et al. Trained immunity in newborn infants of HBV-infected mothers. Nat Commun, 6, 2015, 6588.
37. [37] Kakimi, K., Guidotti, L.G., Koezuka, Y., Chisari, F.V., Natural killer T cell activation inhibits hepatitis B virus replication in vivo. J Exp Med 192 (2000), 921–930.
38. [38] Yang, P.L., Althage, A., Chung, J., Chisari, F.V., Hydrodynamic injection of viral DNA: a mouse model of acute hepatitis B virus infection. Proc Natl Acad Sci USA 99 (2002), 13825–13830.
39. [39] Fisicaro, P., Valdatta, C., Boni, C., Massari, M., Mori, C., Zerbini, A., et al. Early kinetics of innate and adaptive immune responses during Hepatitis B Virus infection. Gut 58 (2009), 974–982.
40. [40] Guy, C.S., Mulrooney-Cousins, P.M., Churchill, N.D., Michalak, T.I., Intrahepatic expression of genes affiliated with innate and adaptive immune responses immediately after invasion and during acute infection with woodchuck hepadnavirus. J Virol 82 (2008), 8579–8591.
41. [41] Webster, G.J., Reignat, S., Maini, M.K., Whalley, S.A., Ogg, G.S., King, A., et al. Incubation phase of acute hepatitis B in man: dynamic of cellular immune mechanisms. Hepatology 32 (2000), 1117–1124.
42. [42] Oliviero, B., Varchetta, S., Paudice, E., Michelone, G., Zaramella, M., Mavilio, D., et al. Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections. Gastroenterology 137 (2009), 1151–1160.
43. [43] Peppa, D., Micco, L., Javaid, A., Kennedy, P.T., Schurich, A., Dunn, C., et al. Blockade of immunosuppressive cytokines restores NK cell antiviral function in chronic hepatitis B virus infection. PLoS Pathog, 6, 2010, e1001227.
44. [44] Tjwa, E.T., van Oord, G.W., Hegmans, J.P., Janssen, H.L., Woltman, A.M., Viral load reduction improves activation and function of natural killer cells in patients with chronic hepatitis B. J Hepatol 54 (2011), 209–218.
45. [45] Okazaki, A., Hiraga, N., Imamura, M., Hayes, C.N., Tsuge, M., Takahashi, S., et al. Severe necroinflammatory reaction caused by natural killer cell-mediated Fas/Fas ligand interaction and dendritic cells in human hepatocyte chimeric mouse. Hepatology 56 (2012), 555–566.
46. [46] Zhang, Z., Zhang, S., Zou, Z., Shi, J., Zhao, J., Fan, R., et al. Hypercytolytic activity of hepatic natural killer cells correlates with liver injury in chronic hepatitis B patients. Hepatology 53 (2011), 73–85.
47. [47] Das, J., Khakoo, S.I., NK cells: tuned by peptide?. Immunol Rev 267 (2015), 214–227.
48. [48] Holzemer, A., Thobakgale, C.F., Jimenez Cruz, C.A., Garcia-Beltran, W.F., Carlson, J.M., van Teijlingen, N.H., et al. Selection of an HLA-C∗03:04-restricted HIV-1 p24 Gag sequence variant is associated with viral escape from KIR2DL3+ natural killer cells: data from an observational cohort in South Africa. PLoS Med, 12, 2015, e1001900.
49. [49] Reeves, R.K., Li, H., Jost, S., Blass, E., Li, H., Schafer, J.L., et al. Antigen-specific NK cell memory in rhesus macaques. Nat Immunol 16 (2015), 927–932.
50. [50] Maini, M.K., Peppa, D., NK cells: a double-edged sword in chronic hepatitis B virus infection. Front Immunol, 4, 2013, 57.
51. [51] Peppa, D., Gill, U.S., Reynolds, G., Easom, N.J., Pallett, L.J., Schurich, A., et al. Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell-mediated deletion. J Exp Med 210 (2013), 99–114.
52. [52] Crome, S.Q., Lang, P.A., Lang, K.S., Ohashi, P.S., Natural killer cells regulate diverse T cell responses. Trends Immunol 34 (2013), 342–349.
53. [53] Waggoner, S.N., Cornberg, M., Selin, L.K., Welsh, R.M., Natural killer cells act as rheostats modulating antiviral T cells. Nature 481 (2012), 394–398.
54. [54] Waggoner, S.N., Reighard, S.D., Gyurova, I.E., Cranert, S.A., Mahl, S.E., Karmele, E.P., et al. Roles of natural killer cells in antiviral immunity. Curr Opin Virol 16 (2015), 15–23.
55. [55] Rydyznski, C., Daniels, K.A., Karmele, E.P., Brooks, T.R., Mahl, S.E., Moran, M.T., et al. Generation of cellular immune memory and B-cell immunity is impaired by natural killer cells. Nat Commun, 6, 2015, 6375.
56. [56] Askenase, M.H., Han, S.J., Byrd, A.L., Morais da Fonseca, D., Bouladoux, N., Wilhelm, C., et al. Bone-marrow-resident NK cells prime monocytes for regulatory function during infection. Immunity 42 (2015), 1130–1142.
57. [57] Gur, C., Doron, S., Kfir-Erenfeld, S., Horwitz, E., Abu-Tair, L., Safadi, R., et al. NKp46-mediated killing of human and mouse hepatic stellate cells attenuates liver fibrosis. Gut 61 (2012), 885–893.
58. [58] Kramer, B., Korner, C., Kebschull, M., Glassner, A., Eisenhardt, M., Nischalke, H.D., 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 56 (2012), 1201–1213.
59. [59] Daussy, C., Faure, F., Mayol, K., Viel, S., Gasteiger, G., Charrier, E., et al. T-bet and Eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow. J Exp Med 211 (2014), 563–577.
60. [60] Paust, S., Gill, H.S., Wang, B.Z., Flynn, M.P., Moseman, E.A., Senman, B., et al. Critical role for the chemokine receptor CXCR6 in NK cell-mediated antigen-specific memory of haptens and viruses. Nat Immunol 11 (2010), 1127–1135.
61. [61] Peng, H., Jiang, X., Chen, Y., Sojka, D.K., Wei, H., Gao, X., et al. Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J Clin Invest 123 (2013), 1444–1456.
62. [62] Sojka, D.K., Plougastel-Douglas, B., Yang, L., Pak-Wittel, M.A., Artyomov, M.N., Ivanova, Y., et al. Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells. Elife, 3, 2014, e01659.
63. [63] Baron, J.L., Gardiner, L., Nishimura, S., Shinkai, K., Locksley, R., Ganem, D., Activation of a nonclassical NKT cell subset in a transgenic mouse model of hepatitis B virus infection. Immunity 16 (2002), 583–594.
64. [64] Zeissig, S., Murata, K., Sweet, L., Publicover, J., Hu, Z., Kaser, A., et al. Hepatitis B virus-induced lipid alterations contribute to natural killer T cell-dependent protective immunity. Nat Med 18 (2012), 1060–1068.
65. [65] Tang, X.Z., Jo, J., Tan, A.T., Sandalova, E., Chia, A., Tan, K.C., et al. IL-7 licenses activation of human liver intrasinusoidal mucosal-associated invariant T cells. J Immunol 190 (2013), 3142–3152.
66. [66] Jakubzick, C., Gautier, E.L., Gibbings, S.L., Sojka, D.K., Schlitzer, A., Johnson, T.E., et al. Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes. Immunity 39 (2013), 599–610.
67. [67] Soehnlein, O., Zernecke, A., Eriksson, E.E., Rothfuchs, A.G., Pham, C.T., Herwald, H., et al. Neutrophil secretion products pave the way for inflammatory monocytes. Blood 112 (2008), 1461–1471.
68. [68] Ginhoux, F., Jung, S., Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol 14 (2014), 392–404.
69. [69] Tacke, F., Zimmermann, H.W., Macrophage heterogeneity in liver injury and fibrosis. J Hepatol 60 (2014), 1090–1096.
70. [70] Zimmermann, H.W., Seidler, S., Nattermann, J., Gassler, N., Hellerbrand, C., Zernecke, A., et al. Functional contribution of elevated circulating and hepatic non-classical CD14CD16 monocytes to inflammation and human liver fibrosis. PLoS One, 5, 2010, e11049.
71. [71] Gehring, A.J., Haniffa, M., Kennedy, P.T., Ho, Z.Z., Boni, C., Shin, A., et al. Mobilizing monocytes to cross-present circulating viral antigen in chronic infection. J Clin Invest 123 (2013), 3766–3776.
72. [72] Boltjes, A., Groothuismink, Z.M., van Oord, G.W., Janssen, H.L., Woltman, A.M., Boonstra, A., Monocytes from chronic HBV patients react in vitro to HBsAg and TLR by producing cytokines irrespective of stage of disease. PLoS One, 9, 2014, e97006.
73. [73] Zhang, J.Y., Zou, Z.S., Huang, A., Zhang, Z., Fu, J.L., Xu, X.S., et al. Hyper-activated pro-inflammatory CD16 monocytes correlate with the severity of liver injury and fibrosis in patients with chronic hepatitis B. PLoS One, 6, 2011, e17484.
74. [74] Bility, M.T., Cheng, L., Zhang, Z., Luan, Y., Li, F., Chi, L., et al. Hepatitis B virus infection and immunopathogenesis in a humanized mouse model: induction of human-specific liver fibrosis and M2-like macrophages. PLoS Pathog, 10, 2014, e1004032.
75. [75] Liaskou, E., Zimmermann, H.W., Li, K.K., Oo, Y.H., Suresh, S., Stamataki, Z., et al. Monocyte subsets in human liver disease show distinct phenotypic and functional characteristics. Hepatology 57 (2013), 385–398.
76. [76] Sitia, G., Iannacone, M., Aiolfi, R., Isogawa, M., van Rooijen, N., Scozzesi, C., et al. Kupffer cells hasten resolution of liver immunopathology in mouse models of viral hepatitis. PLoS Pathog, 7, 2011, e1002061.
77. [77] Wu, J., Lu, M., Meng, Z., Trippler, M., Broering, R., Szczeponek, A., et al. Toll-like receptor-mediated control of HBV replication by nonparenchymal liver cells in mice. Hepatology 46 (2007), 1769–1778.
78. [78] Hosel, M., Quasdorff, M., Wiegmann, K., Webb, D., Zedler, U., Broxtermann, M., et al. Not interferon, but interleukin-6 controls early gene expression in hepatitis B virus infection. Hepatology 50 (2009), 1773–1782.
79. [79] Boltjes, A., van Montfoort, N., Biesta, P.J., Op den Brouw, M.L., Kwekkeboom, J., van der Laan, L.J., et al. Kupffer cells interact with hepatitis B surface antigen in vivo and in vitro, leading to proinflammatory cytokine production and natural killer cell function. J Infect Dis 211 (2015), 1268–1278.
80. [80] Bleriot, C., Dupuis, T., Jouvion, G., Eberl, G., Disson, O., Lecuit, M., Liver-resident macrophage necroptosis orchestrates type 1 microbicidal inflammation and type-2-mediated tissue repair during bacterial infection. Immunity 42 (2015), 145–158.
81. [81] Kinoshita, M., Uchida, T., Sato, A., Nakashima, M., Nakashima, H., Shono, S., et al. Characterization of two F4/80-positive Kupffer cell subsets by their function and phenotype in mice. J Hepatol 53 (2010), 903–910.
82. [82] Klein, I., Cornejo, J.C., Polakos, N.K., John, B., Wuensch, S.A., Topham, D.J., et al. Kupffer cell heterogeneity: functional properties of bone marrow derived and sessile hepatic macrophages. Blood 110 (2007), 4077–4085.
83. [83] Movita, D., van de Garde, M.D., Biesta, P., Kreefft, K., Haagmans, B., Zuniga, E., et al. Inflammatory monocytes recruited to the liver within 24 hours after virus-induced inflammation resemble Kupffer cells but are functionally distinct. J Virol 89 (2015), 4809–4817.
84. [84] Strauss, O., Dunbar, P.R., Bartlett, A., Phillips, A., The immunophenotype of antigen presenting cells of the mononuclear phagocyte system in normal human liver – a systematic review. J Hepatol 62 (2015), 458–468.
85. [85] Pearce, E.L., Pearce, E.J., Metabolic pathways in immune cell activation and quiescence. Immunity 38 (2013), 633–643.
86. [86] Gabrilovich, D.I., Ostrand-Rosenberg, S., Bronte, V., Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 12 (2012), 253–268.
87. [87] Pallett, L.J., Gill, U.S., Quaglia, A., Sinclair, L.V., Jover-Cobos, M., Schurich, A., et al. Metabolic regulation of hepatitis B immunopathology by myeloid-derived suppressor cells. Nat Med 21 (2015), 591–600.
88. [88] Huang, A., Zhang, B., Yan, W., Wang, B., Wei, H., Zhang, F., et al. Myeloid-derived suppressor cells regulate immune response in patients with chronic hepatitis B virus infection through PD-1-induced IL-10. J Immunol 193 (2014), 5461–5469.
89. [89] Sander, L.E., Sackett, S.D., Dierssen, U., Beraza, N., Linke, R.P., Muller, M., et al. Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor cell function. J Exp Med 207 (2010), 1453–1464.
90. [90] Hochst, B., Schildberg, F.A., Sauerborn, P., Gabel, Y.A., Gevensleben, H., Goltz, D., et al. Activated human hepatic stellate cells induce myeloid derived suppressor cells from peripheral blood monocytes in a CD44-dependent fashion. J Hepatol 59 (2013), 528–535.
91. [91] Chou, H.S., Hsieh, C.C., Yang, H.R., Wang, L., Arakawa, Y., Brown, K., et al. Hepatic stellate cells regulate immune response by way of induction of myeloid suppressor cells in mice. Hepatology 53 (2011), 1007–1019.
92. [92] Kong, X., Sun, R., Chen, Y., Wei, H., Tian, Z., GammadeltaT cells drive myeloid-derived suppressor cell-mediated CD8+ T cell exhaustion in hepatitis B virus-induced immunotolerance. J Immunol 193 (2014), 1645–1653.
93. [93] Fang, Z., Li, J., Yu, X., Zhang, D., Ren, G., Shi, B., et al. Polarization of monocytic myeloid-derived suppressor cells by hepatitis B surface antigen is mediated via ERK/IL-6/STAT3 signaling feedback and restrains the activation of T cells in chronic hepatitis B virus infection. J Immunol 195 (2015), 4873–4883.
94. [94] Isogawa, M., Robek, M.D., Furuichi, Y., Chisari, F.V., Toll-like receptor signaling inhibits hepatitis B virus replication in vivo. J Virol 79 (2005), 7269–7272.
95. [95] Guo, H., Jiang, D., Ma, D., Chang, J., Dougherty, A.M., Cuconati, A., et al. Activation of pattern recognition receptor-mediated innate immunity inhibits the replication of hepatitis B virus in human hepatocyte-derived cells. J Virol 83 (2009), 847–858.
96. [96] Menne, S., Tumas, D.B., Liu, K.H., Thampi, L., AlDeghaither, D., Baldwin, B.H., et al. Sustained efficacy and seroconversion with the Toll-like receptor 7 agonist GS-9620 in the Woodchuck model of chronic hepatitis B. J Hepatol 62 (2015), 1237–1245.
97. [97] Lanford, R.E., Guerra, B., Chavez, D., Giavedoni, L., Hodara, V.L., Brasky, K.M., Fosdick, A., et al. GS-9620, an oral agonist of Toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees. Gastroenterology 144 (2013), 1508–1517 [1517 e1501–1510].
98. [98] Gane, E.J., Lim, Y.S., Gordon, S.C., Visvanathan, K., Sicard, E., Fedorak, R.N., et al. The oral toll-like receptor-7 agonist GS-9620 in patients with chronic hepatitis B virus infection. J Hepatol 63 (2015), 320–328.
99. [99] Goulet, M.L., Olagnier, D., Xu, Z., Paz, S., Belgnaoui, S.M., Lafferty, E.I., et al. Systems analysis of a RIG-I agonist inducing broad spectrum inhibition of virus infectivity. PLoS Pathog, 9, 2013, e1003298.
100. [100] Huang, L.R., Wohlleber, D., Reisinger, F., Jenne, C.N., Cheng, R.L., Abdullah, Z., et al. Intrahepatic myeloid-cell aggregates enable local proliferation of CD8(+) T cells and successful immunotherapy against chronic viral liver infection. Nat Immunol 14 (2013), 574–583.
101. [101] Schurich, A., Pallett, L.J., Lubowiecki, M., Singh, H.D., Gill, U.S., Kennedy, P.T., et al. The third signal cytokine IL-12 rescues the anti-viral function of exhausted HBV-specific CD8 T cells. PLoS Pathog, 9, 2013, e1003208.
102. [102] Ji, C., Sastry, K.S., Tiefenthaler, G., Cano, J., Tang, T., Ho, Z.Z., et al. Targeted delivery of interferon-alpha to hepatitis B virus-infected cells using T-cell receptor-like antibodies. Hepatology 56 (2012), 2027–2038.
103. [103] Berraondo, P., Di Scala, M., Korolowicz, K., Thampi, L.M., Otano, I., Suarez, L., et al. Liver-directed gene therapy of chronic hepadnavirus infection using interferon alpha tethered to apolipoprotein A-I. J Hepatol 63 (2015), 329–336.
104. [104] Yan, R., Zhao, X., Cai, D., Liu, Y., Block, T.M., Guo, J.T., et al. The interferon-inducible protein tetherin inhibits hepatitis B virus virion secretion. J Virol 89 (2015), 9200–9212.
105. [105] Lucifora, J., Xia, Y., Reisinger, F., Zhang, K., Stadler, D., Cheng, X., et al. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science 343 (2014), 1221–1228.
106. [106] Fletcher, S.P., Chin, D.J., Gruenbaum, L., Bitter, H., Rasmussen, E., Ravindran, P., et al. Intrahepatic transcriptional signature associated with response to interferon-alpha treatment in the woodchuck model of chronic hepatitis B. PLoS Pathog, 11, 2015, e1005103.
107. [107] Micco, L., Peppa, D., Loggi, E., Schurich, A., Jefferson, L., Cursaro, C., et al. Differential boosting of innate and adaptive antiviral responses during pegylated-interferon-alpha therapy of chronic hepatitis B. J Hepatol 58 (2013), 225–233.
108. [108] Penna, A., Laccabue, D., Libri, I., Giuberti, T., Schivazappa, S., Alfieri, A., et al. Peginterferon-alpha does not improve early peripheral blood HBV-specific T-cell responses in HBeAg-negative chronic hepatitis. J Hepatol 56 (2012), 1239–1246.
109. [109] Davidson, S., Maini, M.K., Wack, A., Disease-promoting effects of type I interferons in viral, bacterial, and coinfections. J Interferon Cytokine Res 35 (2015), 252–264.
110. [110] Boni, C., Laccabue, D., Lampertico, P., Giuberti, T., Vigano, M., Schivazappa, S., et al. Restored function of HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues. Gastroenterology, 143, 2012 963–973.e969.
111. [111] Maini, M.K., Schurich, A., Direct-acting antivirals trump interferon-alpha in their capacity to rescue exhausted T cells upon HCV clearance. J Hepatol 61 (2014), 459–461.
112. [112] Martin, B., Hennecke, N., Lohmann, V., Kayser, A., Neumann-Haefelin, C., Kukolj, G., et al. Restoration of HCV-specific CD8+ T cell function by interferon-free therapy. J Hepatol 61 (2014), 538–543.
113. [113] Stelma, F., de Niet, A., Tempelmans Plat-Sinnige, M.J., Jansen, L., Takkenberg, R.B., Reesink, H.W., et al. Natural killer cell characteristics in patients with chronic hepatitis B virus (HBV) infection are associated with HBV surface antigen clearance after combination treatment with pegylated interferon Alfa-2a and adefovir. J Infect Dis 212 (2015), 1042–1051.
114. [114] Tan, A.T., Hoang, L.T., Chin, D., Rasmussen, E., Lopatin, U., Hart, S., et al. Reduction of HBV replication prolongs the early immunological response to IFNalpha therapy. J Hepatol 60 (2014), 54–61.
115. [115] Thimme, R., Dandri, M., Dissecting the divergent effects of interferon-alpha on immune cells: time to rethink combination therapy in chronic hepatitis B?. J Hepatol 58 (2013), 205–209.
116. [116] Boni, C., Lampertico, P., Talamona, L., Giuberti, T., Invernizzi, F., Barili, V., et al. Natural killer cell phenotype modulation and natural killer/T-cell interplay in nucleos(t)ide analogue-treated hepatitis e antigen-negative patients with chronic hepatitis B. Hepatology 62 (2015), 1697–1709.
117. [117] Rydyznski, C.E., Waggoner, S.N., Boosting vaccine efficacy the natural (killer) way. Trends Immunol 36 (2015), 536–546.
118. [118] Tacke, F., Ginhoux, F., Jakubzick, C., van Rooijen, N., Merad, M., Randolph, G.J., Immature monocytes acquire antigens from other cells in the bone marrow and present them to T cells after maturing in the periphery. J Exp Med 203 (2006), 583–597.
119. [119] Canaday, D.H., Burant, C.J., Jones, L., Aung, H., Woc-Colburn, L., Anthony, D.D., Preserved MHC-II antigen processing and presentation function in chronic HCV infection. Cell Immunol 266 (2011), 187–191.
120. [120] Woc-Colburn, L., Smultea, L., Ramachandra, L., Canaday, D.H., Preserved MHC class II antigen processing in monocytes from HIV-infected individuals. PLoS One, 5, 2010, e9491.
121. [121] De Veirman, K., Van Valckenborgh, E., Lahmar, Q., Geeraerts, X., De Bruyne, E., Menu, E., et al. Myeloid-derived suppressor cells as therapeutic target in hematological malignancies. Front Oncol, 4, 2014, 349.