Дендритные клетки в патогенезе вирусного гепатита С

Инфекция, вызванная вирусом гепатита С (HCV), является серьезной проблемой здравоохранения, поскольку в большинстве случаев (до 85%) приобретает хроническое течение и повышает риск развития цирроза печени, гепатоцеллюлярной карциномы и выраженных внепеченочных осложнений. Причины хронизации инфекции во многом связаны с недостаточностью противовирусного иммунного ответа. Эффективная элиминация вируса требует ранней активации врожденного иммунитета, индукции сильного HCV-специфического мультиэпитопного Т-клеточного ответа и формирования продолжительной иммунологической памяти. Дендритные клетки (DC), которые представляют гетерогенную популяцию антигенпрезентирующих клеток, являются продуцентами интерферонов первого типа, способны активировать натуральные киллерные клетки и индуцировать адаптивный иммунный ответ, выполняя, таким образом, важную роль в противовирусной защите. При этом нарушение функций DC при HCV-инфекции рассматривается в качестве одного из механизмов, позволяющих вирусу избежать иммунного надзора. Настоящий обзор включает современные данные, характеризующие роль DC в иммунном ответе при HCV-инфекции и освещает ряд ключевых вопросов, касающихся изменений фенотипа и функций различных субпопуляций DC у пациентов с вирусным гепатитом С, механизмов нарушения функциональной активности DC и перспектив лечения хронического гепатита С на основе использования генерированных ex vivo DC. 

1. Akira S., Uematsu S., Takeuchi O. Pathogen recognition and innate immunity. Cell, 2006, vol. 124, no. 4, pp. 783–801. doi: 10.1016/j.cell.2006.02.015

2. Andronescu D., Diaconu S., Tiuca N., Purcarea R.M., Andronescu C.I. Hepatitis C treatment and management. J. Med. Life, 2014, vol. 7, no. 1, pp. 31–36.

3. Anthony D.D., Yonkers N.L., Post A.B., Asaad R., Heinzel F.P., Lederman M.M., Lehmann P.V., Valdez H. Selective impairments in dendritic cell-associated function distinguish hepatitis C virus and HIV infection. J. Immunol., 2004, vol. 172, no. 8, pp. 4907–4916. doi: 10.4049/jimmunol.172.8.4907

4. Antonelli A., Ferri C., Galeazzi M., Giannitti C., Manno D., Mieli-Vergani G., Menegatti E., Olivieri I., Puoti M., Palazzi C., Roccatello D., Vergani D., Sarzi-Puttini P., Atzeni F. HCV infection: pathogenesis, clinical manifestations and therapy. Clin. Exp. Rheumatol., 2008, vol. 26 (1 Suppl. 48): S39–47.

5. Auffermann-Gretzinger S., Keeffe E.B., Levy S. Impaired dendritic cell maturation in patients with chronic, but not resolved, hepatitis C virus infection. Blood, 2001, vol. 97, no. 10, pp. 3171–3176. doi: 10.1182/blood.V97.10.3171

6. Bachem A., Guttler S., Hartung E., Ebstein F., Schaefer M., Tannert A., Salama A., Movassaghi K., Opitz C., Mages H.W., Henn V., Kloetzel P.M., Gurka S., Kroczek R.A. Superior antigen cross-presentation and XCR1 expression define human CD11c+CD141+ cells as homologues of mouse CD8+ dendritic cells. J. Exp. Med., 2010, vol. 207, no. 6, pp. 1273–1281. doi: 10.1084/jem.20100348

7. Bain C., Fatmi A., Zoulim F., Zarski J.P., Trepo C., Inchauspe G. Impaired allostimulatory function of dendritic cells in chronic hepatitis C infection. Gastroenterology, 2001, vol. 120, no. 2, pp. 512–524. doi: 10.1053/gast.2001.21212

8. Banchereau J., Briere F., Caux C., Davoust J., Lebecque S., Liu Y.J., Pulendran B., Palucka K. Immunobiology of dendritic cells. Annu Rev Immunol., 2000, vol. 18, pp. 767–811. doi: 10.1146/annurev.immunol.18.1.767

9. Barnes E., Salio M., Cerundolo V., Francesco L., Pardoll D., Klenerman P., Cox A. Monocyte derived dendritic cells retain their functional capacity in patients following infection with hepatitis C virus. J. Viral Hepat., 2008, vol. 15, no. 3, pp. 219–228. doi: 10.1111/j.1365-2893.2007.00934.x

10. Barnes E., Salio M., Cerundolo V., Medlin J., Murphy S., Dusheiko G., Klenerman P. Impact of interferon-α and ribavirin on the function of maturing dendritic cells. Antimicrob. Agents Chemother., 2004, vol. 48, no. 9, pp. 3382–3389. doi: 10.1128/AAC.48.9.3382-3389.2004

11. Barth H., Ulsenheimer A., Pape G.R., Diepolder H.M., Hoffmann M., Neumann-Haefelin C., Thimme R., Henneke P., Klein R., Paranhos-Baccalа G., Depla E., Liang T.J., Blum H.E., Baumert T.F. Uptake and presentation of hepatitis C virus-like particles by human dendritic cells. Blood, 2005, vol. 105, no. 9, pp. 3605–3614. doi: 10.1182/blood-2004-05-1952

12. Bode J.G., Brenndorfer E.D., Haussinger D. Hepatitis C virus (HCV) employs multiple strategies to subvert the host innate antiviral response. Biol Chem., 2008, vol. 389, no. 10, pp. 1283–1298. doi: 10.1515/BC.2008.147

13. Boltjes A., van Wijk F. Human dendritic cell functional specialization in steady-state and inflammation. Front Immunol., 2014, vol. 5: 131. doi: 10.3389/fimmu.2014.00131

14. Brady M.T., MacDonald A.J., Rowan A.G., Mills K.H. Hepatitis C virus non-structural protein 4 suppresses Th1 responses by stimulating IL-10 production from monocytes. Eur. J. Immunol., 2003, vol. 33, no. 12, pp. 3448–3457. doi: 10.1002/eji.200324251

15. Burke K.P., Cox A.L. Hepatitis C virus evasion of adaptive immune responses: a model for viral persistence. Immunol. Res., 2010, vol. 47, no. 1–3, pp. 216–227. doi: 10.1007/s12026-009-8152-3

16. 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., 2011, vol. 266, no. 2, pp. 187–191. doi: 10.1016/j.cellimm.2010.10.003

17. Cheent K., Khakoo S.I. Natural killer cells and hepatitis C: action and reaction. Gut, 2011, vol. 60, no. 2, pp. 268–278. doi: 10.1136/gut.2010.212555

18. Cheng P., Corzo C.A., Luetteke N., Yu B., Nagaraj S., Bui M.M., Ortiz M., Nacken W., Sorg C., Vogl T. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J. Exp. Med., 2008, vol. 205, no. 10, pp. 2235–2249. doi: 10.1084/jem.20080132

19. Collin M., McGovern N., Haniffa M. Human dendritic cell subsets. Immunology, 2013, vol. 140, no. 1, pp. 22–30. doi: 10.1111/imm.12117

20. Crosignani A., Riva A., Della Bella S. Analysis of peripheral blood dendritic cells as a non-invasive tool in the follow-up of patients with chronic hepatitis C. World J. Gastroenterol., 2016, vol. 22, no. 4, pp. 1393–1404. doi: 10.3748/wjg.v22.i4.1393

21. Della Bella S., Crosignani A., Riva A., Presicce P., Benetti A., Longhi R., Podda M., Villa M.L. Decrease and dysfunction of dendritic cells correlate with impaired hepatitis C virus-specific CD4+ T-cell proliferation in patients with hepatitis C virus infection. Immunology, 2007, vol. 121, no. 2, pp. 283–292. doi: 10.1111/j.1365-2567.2007.02577.x

22. Dolganiuc A., Kodys K., Kopasz A., Marshall C., Do T., Romics L. Jr., Mandrekar P., Zapp M., Szabo G. Hepatitis C virus core and nonstructural protein 3 proteins induce proand anti-inflammatory cytokines and inhibit dendritic cell differentiation. J. Immunol., 2003, vol. 170, no. 11, pp. 5615–5624. doi: 10.4049/jimmunol.170.11.5615

23. Dolganiuc A., Paek E., Kodys K., Thomas J., Szabo G. Myeloid dendritic cells of patients with chronic HCV infection induce proliferation of regulatory T lymphocytes. Gastroenterology, 2008, vol. 135, no. 6, pp. 2119–2127. doi: 10.1053/j.gastro.2008.07.082

24. Dolganiuc A., Szabo G. Dendritic cells in hepatitis C infection: can they (help) win the battle? J. Gastroenterol., 2011, vol. 46, no. 4, pp. 432–447. doi: 10.1007/s00535-011-0377-y

25. Dustin L.B., Bartolini B., Capobianchi M.R., Pistello M. Hepatitis C virus: life cycle in cells, infection and host response, and analysis of molecular markers influencing the outcome of infection and response to therapy. Clin. Microbiol. Infect., 2016, vol. 22, no. 10, pp. 826–832. doi: 10.1016/j.cmi.2016.08.025

26. Dustin L.B., Cashman S.B., Laidlaw S.M. Immune control and failure in HCV infection — tipping the balance. J. Leukoc. Biol., 2014, vol. 96, no. 4, pp. 535–548. doi: 10.1189/jlb.4RI0214-126R

27. Dustin L.B., Rice C.M. Flying under the radar: the immunobiology of hepatitis C. Annu. Rev. Immunol., 2007, vol. 25, pp. 71–99. doi: 10.1146/annurev.immunol.25.022106.141602

28. Echeverria I., Pereboev A., Silva L., Zabaleta A., Riezu-Boj J.I., Bes M., Cubero M., Borras-Cuesta F., Lasarte J.J., Esteban J.I., Prieto J., Sarobe P. Enhanced T cell responses against hepatitis C virus by ex vivo targeting of adenoviral particles to dendritic cells. Hepatology, 2011, vol. 54, no. 1, pp. 28–37. doi: 10.1002/hep.24325

29. Fallarino F., Grohmann U., Vacca C., Bianchi R., Orabona C., Spreca A., Fioretti M.C., Puccetti P. T cell apoptosis by tryptophan catabolism. Cell Death Differ., 2002, vol. 9, no. 10, pp. 1069–1077. doi: 10.1038/sj.cdd.4401073

30. Fan Z., Huang X.L., Kalinski P., Young S., Rinaldo C.R. Jr. Dendritic cell function during chronic hepatitis C virus and human immunodeficiency virus type 1 infection. Clin. Vaccine Immunol., 2007, vol. 14, no. 9, pp. 1127–1137. doi: 10.1128/CVI.00141-07

31. Freeman G.J., Long A.J., Iwai Y., Bourque K., Chernova T., Nishimura H., Fitz L.J., Malenkovich N., Okazaki T., Byrne M.C., Horton H.F., Fouser L., Carter L., Ling V., Bowman M.R., Carreno B.M., Collins M., Wood C.R., Honjo T. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med., 2000, vol. 192,no. 7, pp. 1027–1034. doi: 10.1084/jem.192.7.1027

32. Gelderblom H.C., Nijhuis L.E., de Jong E.C., te Velde A.A., Packrat D., Reesink H.W., Beld M.G., van Deventer S.J., Jansen P.L. Monocyte-derived dendritic cells from chronic HCV patients are not infected but show an immature phenotype and aberrant cytokine profile. Liver Int., 2007, vol. 27, no. 7, pp. 944–953. doi: 10.1111/j.1478-3231.2007.01507.x

33. Gowans E.J., Roberts S., Jones К., Dinatale I., Latour P.A., Chua B., Eriksson E.M., Chin R., Li S., Wall D.M., Sparrow R.L., Moloney J., Loudovaris M., Ffrench R., Prince H.M., Hart D., Zeng W., Torresi J., Brown L.E., Jackson D.C. A phase I clinical trial of dendritic cell immunotherapy in HCV-infected individuals. J. Hepatol., 2010, vol. 53, no. 4, pp. 599–607. doi: 10.1016/j.jhep.2010.05.007

34. Guo Z., Zhang H., Rao H., Jiang D., Cong X., Feng B., Wang J., Wei L., Chen H. DCs pulsed with novel HLA-A2-restricted CTL epitopes against hepatitis C virus induced a broadly reactive anti-HCV-secific T lymphocyte response. PLoS One, 2012, vol. 7, no. 6: e38390. doi: 10.1371/journal.pone.0038390

35. Hancharou A.Y., Titov L.P., DuBuske L.M. Altered phenotype and function of monocyte-derived dendritic cells in acute hepatitis C and chronic hepatitis C. J. Allergy Clin. Immunol., 2009, vol. 123, no. 2, S221. doi: 10.1016/j.jaci.2008.12.846

36. Hiet M.S., Bauhofer O., Zayas M., Roth H., Tanaka Y., Schirmacher P., Willemsen J., Grünvogel O., Bender S., Binder M., Lohmann V., Lotteau V., Ruggieri A., Bartenschlager R. Control of temporal activation of hepatitis C virus-induced interferon response by domain 2 of nonstructural protein 5A. J. Hepatol., 2015, vol. 63, no. 4, pp. 829–837. doi: 10.1016/j.jhep.2015.04.015

37. Holz L., Rehermann B. T cell responses in hepatitis C virus infection: historical overview and goals for future research. Antiviral Res., 2015, vol. 114, pp. 96–105. doi: 10.1016/j.antiviral.2014.11.009

38. Imran M., Waheed Y., Manzoor S., Bilal M., Ashraf W., Ali M., Ashraf M. Interaction of hepatitis C virus proteins with pattern recognition receptors. Virol J., 2012, vol. 9: 126. doi: 10.1186/1743-422X-9-126

39. Jinushi M., Takehara T., Kanto T., Tatsumi T., Groh V., Spies T., Miyagi T., Suzuki T., Sasaki Y., Hayashi N. Critical role of MHC class I-related chain A and B expression on IFN-α-stimulated dendritic cells in NK cell activation: impairment in chronic hepatitis C virus infection. J. Immunol., 2003, vol. 170, no. 3, pp. 1249–1256. doi: 10.4049/jimmunol.170.3.1249

40. Joffre O.P. Segura E., Savina A., Amigorena S. Cross-presentation by dendritic cells. Nat. Rev. Immunol., 2012, vol. 12, no. 8, pp. 557–569. doi: 10.1038/nri3254

41. Kadowaki N., Ho S., Antonenko S., Malefyt R.W., Kastelein R.A., Bazan F., Liu Y.J. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J. Exp. Med., 2001, vol. 194, no. 6, pp. 863–869. doi: 10.1084/jem.194.6.863

42. Kanto T., Hayashi N., Takehara T., Tatsumi T., Kuzushita N., Ito A., Sasaki Y., Kasahara A., Hori M. Impaired allostimulatory capacity of peripheral blood dendritic cells recovered from hepatitis C virus-infected individuals. J. Immunol., 1999, vol. 162, no. 9, pp. 5584–5591.

43. Kanto T., Inoue M., Miyatake H., Sato A., Sakakibara M., Yakushijin T., Oki C., Itose I., Hiramatsu N., Takehara T. Reduced numbers and impaired ability of myeloid and plasmacytoid dendritic cells to polarize T helper cells in chronic hepatitis C virus infection. J. Infect. Dis., 2004, vol. 190, no. 11, pp. 1919–1926. doi: 10.1086/425425

44. Kanto T., Inoue M., Miyazaki M., Itose I., Miyatake H., Sakakibara M., Yakushijin T., Kaimori A., Oki C., Hiramatsu N., Kasahara A., Hayashi N. Impaired function of dendritic cells circulating in patients infected with hepatitis C virus who have persistently normal alanine aminotransferase levels. Intervirology, 2006, vol. 49, no. 1–2, pp. 58–63. doi: 10.1159/000087264

45. Kaplan D.E. Immunopathogenesis of hepatitis C virus infection. Gastroenterol. Clin. North Am., 2015, vol. 44, no. 4, pp. 735–760. doi: 10.1016/j.gtc.2015.07.004

46. Klechevsky E., Flamar A.L., Cao Y., Blanck J.P., Liu M., O’Bar A., Agouna-Deciat O., Klucar P., Thompson-Snipes L., Zurawski S., Reiter Y., Palucka A.K., Zurawski G., Banchereau J. Cross-priming CD8+ T cells by targeting antigens to human dendritic cells through DCIR. Blood, 2011, vol. 116, no. 10, pp. 1685–1697. doi: 10.1182/blood-2010-01-264960

47. Krebs D.L., Hilton D.J. SOCS proteins: negative regulators of cytokine signaling. Stem Cells., 2001, vol. 19, no. 5, pp. 378–387. doi: 10.1634/stemcells.19-5-378

48. Krishnadas D.K., Ahn J.S., Han J., Kumar R., Agrawal B. Immunomodulation by hepatitis C virus-derived proteins: targeting human dendritic cells by multiple mechanisms. Int. Immunol., 2010, vol. 22, no. 6, pp. 491–502. doi: 10.1093/intimm/dxq033

49. Kunitani H., Shimizu Y., Murata H., Higuchi K., Watanabe A. Phenotypic analysis of circulating and intrahepatic dendritic cell subsets in patients with chronic liver diseases. J. Hepatol., 2002, vol. 36, no. 6, pp. 734–741. doi: 10.1016/S0168-8278(02)00062-4

50. Landi A., Babiuk L.A., van Drunen Litte, van den Hurk S. Dendritic cells matured by a prostaglandin E2-containing cocktail can produce high levels of IL-12p70 and are more mature and Th1-biased than dendritic cells treated with TNF-α or LPS. Immunobiology, 2011, vol. 216, no. 6, pp. 649–662. doi: 10.1016/j.imbio.2010.11.004

51. Lechner F., Wong D.K., Dunbar P.R., Chapman R., Chung R.T., Dohrenwend P., Robbins G., Phillips R., Klenerman P., Walker B.D. Analysis of successful immune responses in persons infected with hepatitis C virus. J. Exp. Med., 2000, vol. 191, no. 9, pp. 1499–1512. doi: 10.1084/jem.191.9.1499

52. Lester S.N., Li K. Toll-like receptors in antiviral innate immunity. J. Mol. Biol., 2014, vol. 426, no. 6, pp. 1246–1264. doi: 10.1016/j. jmb.2013.11.024

53. Li W., Krishnadas D.K., Li J., Tyrrell D.L., Agrawal B. Induction of primary human T cell responses against hepatitis C virusderived antigens NS3 or core by autologous dendritic cells expressing hepatitis C virus antigens: potential for vaccine and immunotherapy. J. Immunol., 2006, vol. 176, no. 10, pp. 6065–6075. doi: 10.4049/jimmunol.176.10.6065

54. Li W., Li J., Tyrrell D.L.J., Agrawal B. Expression of hepatitis C virus (HCV) derived Core or NS3 antigens in human dendritic cells leads to induction in pro-inflammatory cytokines and normal T cell stimulation capabilities. J. Gen. Virol., 2006, vol. 87, pp. 61–72. doi: 10.1099/vir.0.81364-0

55. Li Y., Chu N., Rostami A., Zhang G.X. Dendritic cells transduced with SOCS-3 exhibit a tolerogenic/DC2 phenotype that directs type 2 Th cell differentiation in vitro and in vivo. J. Immunol., 2006, vol. 177, no. 3, pp. 1679–1688. doi: 10.4049/jimmunol.177.3.1679

56. Longman R.S., Talal A.H., Jacobson I.M., Albert M.L., Rice C.M. Presence of functional dendritic cells in patients chronically infected with hepatitis C virus. Blood, 2004, vol. 103, no. 3, pp. 1026–1029. doi: 10.1182/blood-2003-04-1339

57. Longman R.S., Talal A.H., Jacobson I.M., Rice C.M., Albert M.L. Normal functional capacity in circulating myeloid and plasmacytoid dendritic cells in patients with chronic hepatitis C. J. Infect. Dis., 2005, vol. 192, no. 3, pp. 497–503. doi: 10.1086/431523

58. Ludwig I.S., Lekkerkerker A.N., Depla E., Bosman F., Musters R.J.P., Depraetere S., van Kooyk Y., Geijtenbeek T.B.H. Hepatitis C virus targets DC-SIGN and L-SIGN to escape lysosomal degradation. J. Virol., 2004, vol. 78, no. 15, pp. 8322–8332. doi: 10.1128/JVI.78.15.8322-8332.2004

59. Manns M.P., Buti M., Gane E., Pawlotsky J.M., Razavi H., Terrault N., Younossi Z. Hepatitis C virus infection. Nat. Rev. Dis. Primers., 2017, vol. 3: 17006. doi: 10.1038/nrdp.2017.6

60. Mishra S., Losikoff P.T., Self A.A., Terry F., Ardito M.T., Tassone R., Martin W.D., De Groot A.S., Gregory S.H. Peptidepulsed dendritic cells induce the hepatitis C viral epitope-specific responses of naїve human T cells. Vaccine, 2014, vol. 32, no. 26, pp. 3285–3292. doi: 10.1016/j.vaccine.2014.03.083

61. Miyazaki M., Kanto T., Inoue M., Itose I., Miyatake H., Sakakibara M., Yakushijin T., Kakita N., Hiramatsu N., Takehara T., Kasahara A., Hayashi N. Impaired cytokine response in myeloid dendritic cells in chronic hepatitis C virus infection regardless of enhanced expression of Toll-like receptors and retinoic acid inducible gene-I. J. Med. Virol., 2008, vol. 80, no. 6, pp. 980–988. doi: 10.1002/jmv.21174

62. Murakami H., Akbar S.M., Matsui H., Horiike N., Onji M. Decreased interferon-alpha production and impaired T helper 1 polarization by dendritic cells from patients with chronic hepatitis C. Clin. Exp. Immunol., 2004, vol. 137, no. 3, pp. 559–565. doi: 10.1111/j.1365-2249.2004.02550.x

63. Neumann-Haefelin C., Thimme R. Success and failure of virus-specific T cell responses in hepatitis C virus infection. Dig. Dis., 2011, vol. 29, no. 4, pp. 416–422. doi: 10.1159/000329807

64. Nierkens S., Tel J., Janssen E., Adema G.J. Antigen cross-presentation by dendritic cell subsets: one general or all sergeants? Trends Immunol., 2013, vol. 34, no. 8, pp. 361–370. doi: 10.1016/j.it.2013.02.007

65. Obregon C., Kumar R., Pascual M.A., Vassalli G., Golshayan D. Update on dendritic cell-induced immunological and clinical tolerance. Front Immunol., 2017, vol. 8: 1514. doi: 10.3389/fimmu.2017.01514

66. Pelletier S., Bédard N., Said E., Ancuta P., Bruneau J., Shoukry N.H. Sustained hyperresponsiveness of dendritic cells is associated with spontaneous resolution of acute hepatitis C. J. Virol., 2013, vol. 87, no. 12, pp. 6769–6781. doi: 10.1128/JVI.02445-12

67. Perrella A., Atripaldi L., Bellopede P., Patarino T., Sbreglia C., Tarantino G., Sorrentino P., Conca P., Ruggiero L., Perrella O. Flow cytometry assay of myeloid dendritic cells (mDCs) in peripheral blood during acute hepatitis C: possible pathogenetic mechanisms. World J. Gastroenterol., 2006, vol. 12, no. 7, pp. 1105–1109. doi: 10.3748/wjg.v12.i7.1105

68. Perrin-Cocon L., Agaugué S., Diaz O., Vanbervliet B., Dollet S., Guironnet-Paquet A., André P., Lotteau V. Th1 disabled function in response to TLR4 stimulation of monocyte-derived DC from patients chronically-infected by hepatitis C virus. PLoS One, 2008, vol. 3, no. 5: e2260. doi: 10.1371/journal.pone.0002260

69. Piccioli D., Tavarini S., Nuti S., Colombatto P., Brunetto M., Bonino F., Ciccorossi P., Zorat F., Pozzato G., Comar C. Comparable functions of plasmacytoid and monocyte-derived dendritic cells in chronic hepatitis C patients and healthy donors. J. Hepatol., 2005, vol. 42, no. 1, pp. 61–67. doi: 10.1016/j.jhep.2004.09.014

70. Racanelli V., Manigold T. Presentation of HCV antigens to naive CD8+ T cells: why the where, when, what and how are important for virus control and infection outcome. Clin. Immunol., 2007, vol. 124, no. 1, pp. 5–12. doi: 10.1016/j.clim.2007.04.009

71. Rana D., Chawla Y.K., Duseja A., Dhiman R.K., Arora S.K. Viral proteins mediate upregulation of negative regulatory factors causing down-modulated dendritic cell functions in chronic hepatitis C virus infection. EMJ Hepatology, 2013, vol. 1, pp. 68–76.

72. Reis e Sousa C. Dendritic cells in a mature age. Nat. Rev. Immunol., 2006, vol. 6, no. 6, pp. 476 483. doi: 10.1038/nri1845

73. Rodrigue-Gervais I.G., Rigsby H., Jouan L., Sauvé D., Sékaly R.P., Willems B., Lamarre D. Dendritic cell inhibition is connected to exhaustion of CD8+ T cell polyfunctionality during chronic hepatitis C virus infection. J. Immunol., 2010, vol. 184, no. 6, pp. 3134–3144. doi: 10.4049/jimmunol.0902522

74. Roohvand F., Kossari N. Advances in hepatitis C virus vaccines, part two: advances in hepatitis C virus vaccine formulations and modalities. Expert Opin. Ther. Pat., 2012, vol. 22, no. 4, pp. 391–415. doi: 10.1517/13543776.2012.673589

75. Ryan E.J., O’Farrelly C. The affect of chronic hepatitis C infection on dendritic cell function: a summary of the experimental evidence. J. Viral Hepat., 2011, vol. 18, no. 9, pp. 601–607. doi: 10.1111/j.1365-2893.2011.01453.x

76. Saha В., Szabo G. Innate immune cell networking in hepatitis C virus infection. J. Leukoc. Biol., 2014, vol. 96, no. 5, pp. 757–766. doi: 10.1189/jlb.4MR0314-141R

77. Saito K., Ait-Goughoulte M., Truscott S.M., Meyer K., Blazevic A., Abate G., Ray R.B., Hoft D.F., Ray R. Hepatitis C virus inhibits cell surface expression of HLA-DR, prevents dendritic cell maturation, and induces interleukin-10 production. J. Virol., 2008, vol. 82, no. 7, pp. 3320–3328. doi: 10.1128/JVI.02547-07

78. Santantonio T., Wiegand J., Gerlach J.T. Acute hepatitis C: current status and remaining challenges. J. Hepatol., 2008, vol. 49, no. 4, pp. 625–633. doi: 10.1016/j.jhep.2008.07.005

79. Sarobe P., Lasarte J.J., Casares N., López-Díaz de Cerio A., Baixeras E., Labarga P., García N., Borrás-Cuesta F., Prieto J. Abnormal priming of CD4+ T cells by dendritic cells expressing hepatitis C virus core and E1 proteins. J. Virol., 2002, vol. 76, no. 10, pp. 5062–5070. doi: 10.1128/JVI.76.10.5062-5070.2002

80. Schulz S., Landi A., Garg R., Wilson J.A., van Drunen Littel-van den Hurk S. Indolamine 2,3-dioxygenase expression by monocytes and dendritic cell populations in hepatitis C patients. Clin. Exp. Immunol., 2015, vol. 180, no. 3, pp. 484–498. doi: 10.1111/cei.12586

81. Semmo N., Klenerman P. CD4+ T cell responses in hepatitis C virus infection. World J. Gastroenterol., 2007, vol. 13, no. 36, pp. 4831–4838. doi: 10.3748/wjg.v13.i36.4831

82. Shen T., Chen X., Chen Y., Xu Q., Lu F., Liu S. Increased PD-L1 expression and PD-L1/CD86 ratio on dendritic cells were associated with impaired dendritic cells function in HCV infection. J. Med. Virol., 2010, vol. 82, no. 7, pp. 1152–1159. doi: 10.1002/jmv.21809

83. Smith D.B., Bukh J., Kuiken C., Muerhoff A.S., Rice C.M., Stapleton J.T., Simmonds P. Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: updated criteria and genotype assignment web resource. Hepatology, 2014, vol. 59, no. 1, pp. 318–327. doi: 10.1002/hep.26744

84. Stone A.E., Giugliano S., Schnell G., Cheng L., Leahy K.F., Golden-Mason L., Gale M. Jr., Rosen H.R. Hepatitis C virus pathogen associated molecular pattern (PAMP) triggers production of lambda-interferons by human plasmacytoid dendritic cells. PLoS Pathog., 2013, vol. 9, no. 4: e1003316. doi: 10.1371/journal.ppat.1003316

85. Szabo G., Dolganiuc A. Hepatitis C and innate immunity: recent advances. Clin. Liver Dis., 2008, vol. 12, no. 3, pp. 675–692. doi: 10.1016/j.cld.2008.03.003

86. Szabo G., Dolganiuc A. Subversion of plasmacytoid and myeloid dendritic cell functions in chronic HCV infection. Immunobiology, 2005, vol. 210, no. 2–4, pp. 237–247. doi: 10.1016/j.imbio.2005.05.018

87. Tacke R.S., Tosello-Trampont A., Nguyen V., Mullins D.W., Hahn Y.S. Extracellular hepatitis C virus core protein activates STAT3 in human monocytes/macrophages/dendritic cells via an IL-6 autocrine pathway. J. Biol. Chem., 2011, vol. 286, no. 12, pp. 10847–10855. doi: 10.1074/jbc.M110.217653

88. Takahashi K., Asabe S., Wieland S., Garaigorta U., Gastaminza P., Isogawa M., Chisari F.V. Plasmacytoid dendritic cells sense hepatitis C virus-infected cells, produce interferon, and inhibit infection. Proc. Natl. Acad. Sci. USA, 2010, vol. 107, no. 16, pp. 7431–7436. doi: 10.1073/pnas.1002301107

89. Thaiss C., Semmling V., Franken L., Wagner H., Kurts C. Chemokines: a new dendritic cell signal for T cell activation. Front Immunol., 2011, vol. 2: 31. doi: 10.3389/fimmu.2011.00031

90. Tu Z., Hamalainen-Laanaya H.K., Nishitani C., Kuroki Y., Crispe I.N., Orloff M.S. HCV core and NS3 proteins manipulate human blood-derived dendritic cell development and promote Th 17 differentiation. Int. Immunol., 2012, vol. 24, no. 2, pp. 97–106. doi: 10.1093/intimm/dxr104

91. Ulsenheimer A., Gerlach J.T., Jung M.C., Gruener N., Wachtler M., Backmund M., Santantonio T., Schraut W., Heeg M.H., Schirren C.A., Zachoval R., Pape G.R., Diepolder H.M. Plasmacytoid dendritic cells in acute and chronic hepatitis C virus infection. Hepatology, 2005, vol. 41, no. 3, pp. 643–651. doi: 10.1002/hep.20592

92. Urbani S., Amadei B., Tola D., Pedrazzi G., Sacchelli L., Cavallo M.C., Orlandini A., Missale G., Ferrari C. Restoration of HCVspecific T cell functions by PD-1/PD-L1 blockade in HCV infection: effect of viremia levels and antiviral treatment. J. Hepatol., 2008, vol. 48, no. 4, pp. 548–558. doi: 10.1016/j.jhep.2007.12.014

93. Vivier E., Raulet D.H., Moretta A., Caligiuri M.A., Zitvogel L., Lanier L.L., Yokoyama W.M., Ugolini S. Innate or adaptive immunity? The example of natural killer cells. Science, 2011, vol. 331, no. 6013, pp. 44–49. doi: 10.1126/science.1198687

94. Waggoner S.N., Hall C.H., Hahn Y.S. 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, vol. 82, no. 6, pp. 1407–1419. doi: 10.1189/jlb.0507268

95. Wertheimer A.M., Bakke A., Rosen H.R. Direct enumeration and functional assessment of circulating dendritic cells in patients with liver disease. Hepatology, 2004, vol. 40, no. 2, pp. 335–345. doi: 10.1002/hep.20306

96. Wilby K.J., Partovi N., Ford J.A., Greanya E., Yoshida E.M. Review of boceprevir and telaprevir for the treatment of chronic hepatitis C. Can. J. Gastroenterol., 2012, vol. 26, no. 4, pp. 205–210.

97. Yonkers N.L., Rodriguez B., Milkovich K.A., Asaad R., Lederman M.M., Heeger P.S., Anthony D.D. TLR ligand-dependent activation of naive CD4 T cells by plasmacytoid dendritic cells is impaired in hepatitis C virus infection. J. Immunol,. 2007, vol. 178, no. 7, pp. 4436–4444. doi: 10.4049/jimmunol.178.7.4436

98. Yoshio S., Kanto T., Kuroda S., Matsubara T., Higashitani K., Kakita N. Human blood dendritic cell antigen 3 (BDCA3)(+) dendritic cells are a potent producer of interferon-lambda in response to hepatitis C virus. Hepatology, 2013, vol. 57, no. 5, pp. 1705– 1715. doi: 10.1002/hep.26182

99. Zabaleta A., D’Avola D., Echeverria I., Llopiz D., Silva L., Villanueva L., Riezu-Boj J.I., Larrea E., Pereboev A., Lasarte J.J., Rodriguez-Lago I., Iсarrairaegui M., Sangro B., Prieto J., Sarobe P. Clinical testing of a dendritic cell targeted therapeutic vaccine in patients with chronic hepatitis C virus infection. Mol. Ther. Methods Clin. Dev., 2015, vol. 2: 15006. doi: 10.1038/mtm.2015.6

100. Zhang S., Kodys K., Li K., Szabo G. Human type 2 myeloid dendritic cells produce interferon-λ and amplify interferon-α in response to hepatitis C virus infection. Gastroenterology, 2013, vol. 144, no. 2, pp. 414–425. doi: 10.1053/j.gastro.2012.10.034

101. Zhang Z., Wang F.S. Plasmacytoid dendritic cells act as the most competent cell type in linking antiviral innate and adaptive immune responses. Cell. Mol. Immunol., 2005, vol. 2, no. 6, pp. 411–417.

102. Ziegler-Heitbrock L., Ancuta P., Crowe S., Dalod M., Grau V., Hart D.N., Leenen P.J., Liu Y.J., MacPherson G., Randolph G.J., Scherberich J., Schmitz J., Shortman K., Sozzani S., Strobl H., Zembala M., Austyn J.M., Lutz M.B. Nomenclature of monocytes and dendritic cells in blood. Blood, 2010, vol. 116, no. 16: e74–80. doi: 10.1182/blood-2010-02-258558