Browse > Article
http://dx.doi.org/10.4110/in.2013.13.5.168

The Natural Killer Cell Response to HCV Infection  

Ahlenstiel, Golo (Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney)
Publication Information
IMMUNE NETWORK / v.13, no.5, 2013 , pp. 168-176 More about this Journal
Abstract
In the last few years major progress has been made in better understanding the role of natural killer (NK) cells in hepatitis C virus (HCV) infection. This includes multiple pathways by which HCV impairs or limits NK cells activation. Based on current genetic and functional data, a picture is emerging where only a rapid and strong NK cell response early on during infection which results in strong T cell responses and possible subsequent clearance, whereas chronic HCV infection is associated with dysfunctional or biased NK cells phenotypes. The hallmark of this NK cell dysfunction is persistent activation promoting ongoing hepatitis and hepatocyte damage, while being unable to clear HCV due to impaired IFN-${\gamma}$ responses. Furthermore, some data suggests certain chronically activated subsets that are $NKp46^{high}$ may be particularly active against hepatic stellate cells, a key player in hepatic fibrogenesis. Finally, the role of NK cells during HCV therapy, HCV recurrence after liver transplant and hepatocellular carcinoma are discussed.
Keywords
Natural killer cell; Hepatitis C virus; Viral hepatitis; Chronic infection;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Ljunggren, H. G. and K. Karre. 1990. In search of the 'missing self': MHC molecules and NK cell recognition. Immunol Today. 11: 237-244.   DOI
2 Cantoni, C., C. Bottino, M. Vitale, A. Pessino, R. Augugliaro, A. Malaspina, S. Parolini, L. Moretta, A. Moretta, and R. Biassoni. 1999. NKp44, a triggering receptor involved in tumor cell lysis by activated human natural killer cells, is a nov el member of the immunoglobulin superfamily. J. Exp. Med. 189: 787-796.   DOI
3 Hata, K., X. R. Zhang, S. Iwatsuki, D. H. Van Thiel, R. B. Herberman, and T. L. Whiteside. 1990. Isolation, phenotyping, and functional analysis of lymphocytes from human liver. Clin. Immunol. Immunopathol. 56: 401-419.   DOI
4 Doherty, D. G. and C. O'Farrelly. 2000. Innate and adaptive lymphoid cells in the human liver. Immunol. Rev. 174: 5-20.   DOI
5 Crotta, S., A. Stilla, A. Wack, A. D'Andrea, S. Nuti, U. D'Oro, M. Mosca, F. Filliponi, R. M. Brunetto, F. Bonino, S. Abrignani, and N. M. Valiante. 2002. Inhibition of natural killer cells through engagement of CD81 by the major hepatitis C virus envelope protein. J. Exp. Med. 195: 35-41.   DOI
6 Tseng, C. T. and G. R. Klimpel. 2002. Binding of the hepatitis C virus envelope protein E2 to CD81 inhibits natural killer cell functions. J. Exp. Med. 195: 43-49.   DOI
7 Crotta, S., M. Brazzoli, D. Piccioli, N. M. Valiante, and A. Wack. 2010. Hepatitis C virions subvert natural killer cell activation to generate a cytokine environment permissive for infection. J. Hepatol. 52: 183-190.
8 Yoon, J. C., M. Shiina, G. Ahlenstiel, and B. Rehermann. 2009. Natural killer cell function is intact after direct exposure to infectious hepatitis C virions. Hepatology 49: 12-21.   DOI
9 Nattermann, J., H. D. Nischalke, V. Hofmeister, G. Ahlenstiel, H. Zimmermann, L. Leifeld, E. H. Weiss, T. Sauerbruch, and U. Spengler. 2005. The HLA-A2 restricted T cell epitope HCV core 35-44 stabilizes HLA-E expression and inhibits cytolysis mediated by natural killer cells. Am. J. Pathol. 166: 443-453.   DOI
10 Larkin, J., A. Bost, J. I. Glass, and S. L. Tan. 2006. Cytokine-activated natural killer cells exert direct killing of hepatoma cells harboring hepatitis C virus replicons. J. Interferon Cytokine Res. 26: 854-865.   DOI
11 Yoon, J. C., J. B. Lim, J. H. Park, and J. M. Lee. 2011. Cell-to-cell contact with hepatitis C virus-infected cells reduces functional capacity of natural killer cells. J. Virol. 85: 12557-12569.   DOI
12 Wang, J. M., Y. Q. Cheng, L. Shi, R. S. Ying, X. Y. Wu, G. Y. Li, J. P. Moorman, and Z. Q. Yao. 2013. KLRG1 negatively regulates natural killer (NK) cell functions through Akt pathway in individuals with chronic hepatitis C. J. Virol. 87: 11626-11636.   DOI
13 Holder, K. A., S. N. Stapleton, M. E. Gallant, R. S. Russell, and M. D. Grant. 2013. Hepatitis C Virus-Infected Cells Downregulate NKp30 and Inhibit Ex Vivo NK Cell Functions. J. Immunol. 191: 3308-3318.   DOI
14 Nattermann, J., G. Feldmann, G. Ahlenstiel, B. Langhans, T. Sauerbruch, and U. Spengler. 2006. Surface expression and cytolytic function of natural killer cell receptors is altered in chronic hepatitis C. Gut. 55: 869-877.   DOI
15 Alter, G., S. Jost, S. Rihn, L. L. Reyor, B. E. Nolan, M. Ghebremichael, R. Bosch, M. Altfeld, and G. M. Lauer. 2011. Reduced frequencies of NKp30＋NKp46＋, CD161＋, and NKG2D＋ NK cells in acute HCV infection may predict viral clearance. J. Hepatol. 55: 278-288.   DOI
16 Stegmann, K. A., N. K. Bjorkstrom, S. Ciesek, S. Lunemann, J. Jaroszewicz, J. Wiegand, P. Malinski, L. B. Dustin, C. M. Rice, M. P. Manns, T. Pietschmann, M. Cornberg, H. G. Ljunggren, and H. Wedemeyer. 2012. Interferon alpha-stimulated natural killer cells from patients with acute hepatitis C virus (HCV) infection recognize HCV-infected and uninfected hepatoma cells via DNAX accessory molecule-1. J. Infect. Dis. 205: 1351-1362.   DOI
17 Golden-Mason, L., L. Madrigal-Estebas, E. McGrath, M. J. Conroy, E. J. Ryan, J. E. Hegarty, C. O'Farrelly, and D. G. Doherty. 2008. Altered natural killer cell subset distributions in resolved and persistent hepatitis C virus infection following single source exposure. Gut. 57: 1121-1128.   DOI
18 De Maria, A., M. Fogli, S. Mazza, M. Basso, A. Picciotto, P. Costa, S. Congia, M. C. Mingari, and L. Moretta. 2007. Increased natural cytotoxicity receptor expression and relevant IL-10 production in NK cells from chronically infected viremic HCV patients. Eur. J. Immunol. 37: 445-455.   DOI
19 Oliviero, B., S. Varchetta, E. Paudice, G. Michelone, M. Zaramella, D. Mavilio, F. De Filippi, S. Bruno, and M. U. Mondelli. 2009. Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections. Gastroenterology 137: 1151-1160.   DOI
20 Zhang, S., B. Saha, K. Kodys, and G. Szabo. 2013. IFN-gamma production by human natural killer cells in response to HCV-infected hepatoma cells is dependent on accessory cells. J. Hepatol. 59: 442-449.   DOI
21 Sene, D., F. Levasseur, M. Abel, M. Lambert, X. Camous, C. Hernandez, V. Pene, A. R. Rosenberg, E. Jouvin-Marche, P. N. Marche, P. Cacoub, and S. Caillat-Zucman. 2010. Hepatitis C virus (HCV) evades NKG2D-dependent NK cell responses through NS5A-mediated imbalance of inflammatory cytokines. PLoS Pathog. 6: e1001184.s   DOI
22 Knapp, S., U. Warshow, K. M. Ho, D. Hegazy, A. M. Little, A. Fowell, G. Alexander, M. Thursz, M. Cramp, and S. I. Khakoo. 2011. A polymorphism in IL28B distinguishes exposed, uninfected individuals from spontaneous resolvers of HCV infection. Gastroenterology 141: 320-325.   DOI
23 Suppiah, V., S. Gaudieri, N. J. Armstrong, K. S. O'Connor, T. Berg, M. Weltman, M. L. Abate, U. Spengler, M. Bassendine, G. J. Dore, W. L. Irving, E. Powell, M. Hellard, S. Riordan, G. Matthews, D. Sheridan, J. Nattermann, A. Smedile, T. Muller, E. Hammond, D. Dunn, F. Negro, P. Y. Bochud, S. Mallal, G. Ahlenstiel, G. J. Stewart, J. George, and D. R. Booth. 2011. IL28B, HLA-C, and KIR variants additively predict response to therapy in chronic hepatitis C virus infection in a European Cohort: a cross-sectional study. PLoS Med. 8: e1001092.   DOI
24 Knapp, S., U. Warshow, D. Hegazy, L. Brackenbury, I. N. Guha, A. Fowell, A. M. Little, G. J. Alexander, W. M. Rosenberg, M. E. Cramp, and S. I. Khakoo. 2010. Consistent beneficial effects of killer cell immunoglobulin-like receptor 2DL3 and group 1 human leukocyte antigen-C following exposure to hepatitis C virus. Hepatology 51: 1168-1175.   DOI
25 Khakoo, S. I., C. L. Thio, M. P. Martin, C. R. Brooks, X. Gao, J. Astemborski, J. Cheng, J. J. Goedert, D. Vlahov, M. Hilgartner, S. Cox, A. M. Little, G. J. Alexander, M. E. Cramp, S. J. O'Brien, W. M. Rosenberg, D. L. Thomas, M. Carrington. 2004. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science 305: 872-874.   DOI
26 Thomas, D. L., C. L. Thio, M. P. Martin, Y. Qi, D. Ge, C. O'Huigin, J. Kidd, K. Kidd, S. I. Khakoo, G. Alexander, J. J. Goedert, G. D. Kirk, S. M. Donfield, H. R. Rosen, L. H. Tobler, M. P. Busch, J. G. McHutchison, D. B. Goldstein, and M. Carrington. 2009. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 461: 798-801.   DOI
27 Ge, D., J. Fellay, A. J. Thompson, J. S. Simon, K. V. Shianna, T. J. Urban, E. L. Heinzen, P. Qiu, A. H. Bertelsen, A. J. Muir, M. Sulkowski, J. G. McHutchison, and D. B. Goldstein. 2009. Genetic variation in IL28B predicts hepatitis C treatment- induced viral clearance. Nature 461: 399-401.   DOI
28 Grebely, J., K. Petoumenos, M. Hellard, G. V. Matthews, V. Suppiah, T. Applegate, B. Yeung, P. Marks, W. Rawlinson, A. R. Lloyd, D. Booth, J. M. Kaldor, J. George, and G. J. Dore. 2010. Potential role for interleukin-28B genotype in treatment decision-making in recent hepatitis C virus infection. Hepatology 52: 1216-1224.   DOI
29 Suppiah, V., M. Moldovan, G. Ahlenstiel, T. Berg, M. Weltman, M. L. Abate, M. Bassendine, U. Spengler, G. J. Dore, E. Powell, S. Riordan, D. Sheridan, A. Smedile, V. Fragomeli, T. Muller, M. Bahlo, G. J. Stewart, D. R. Booth, and J. George. 2009. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat. Genet. 41: 1100-1104.   DOI
30 Tanaka, Y., N. Nishida, M. Sugiyama, M. Kurosaki, K. Matsuura, N. Sakamoto, M. Nakagawa, M. Korenaga, K. Hino, S. Hige, Y. Ito, E. Mita, E. Tanaka, S. Mochida, Y. Murawaki, M. Honda, A. Sakai, Y. Hiasa, S. Nishiguchi, A. Koike, I. Sakaida, M. Imamura, K. Ito, K. Yano, N. Masaki, F. Sugauchi, N. Izumi, K. Tokunaga, and M. Mizokami. 2009. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat. Genet. 41: 1105-1109.   DOI
31 Herzer, K., C. S. Falk, J. Encke, S. T. Eichhorst, A. Ulsenheimer, B. Seliger, and P. H. Krammer. 2003. Upregulation of major histocompatibility complex class I on liver cells by hepatitis C virus core protein via p53 and TAP1 impairs natural killer cell cytotoxicity. J. Virol. 77: 8299-8309.   DOI
32 Ahlenstiel, G., M. P. Martin, X. Gao, M. Carrington, and B. Rehermann. 2008. Distinct KIR/HLA compound genotypes affect the kinetics of human antiviral natural killer cell responses. J. Clin. Invest. 118: 1017-1026.
33 Naggie, S., A. Osinusi, A. Katsounas, R. Lempicki, E. Herrmann, A. J. Thompson, P. J. Clark, K. Patel, A. J. Muir, J. G. McHutchison, J. F. Schlaak, M. Trippler, B. Shivakumar, H. Masur, M. A. Polis, and S. Kottilil. 2012. Dysregulation of innate immunity in HCV genotype 1 IL28B unfavorable genotype patients: impaired viral kinetics and therapeutic response. Hepatology 56: 444-454.   DOI
34 Shin, E. C., U. Seifert, T. Kato, C. M. Rice, S. M. Feinstone, P. M. Kloetzel, and B. Rehermann. 2006. Virus-induced type I IFN stimulates generation of immunoproteasomes at the site of infection. J. Clin. Invest. 116: 3006-3014.   DOI
35 Thimme, R., J. Bukh, H. C. Spangenberg, S. Wieland, J. Pemberton, C. Steiger, S. Govindarajan, R. H. Purcell, and F. V. Chisari. 2002. Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease. Proc. Natl. Acad. Sci. USA 99: 15661-15668.   DOI
36 Guidotti, L. G. and F. V. Chisari. 1996. To kill or to cure: options in host defense against viral infection. Curr. Opin. Immunol. 8: 478-483.   DOI
37 Golden-Mason, L., K. M. Bambha, L. Cheng, C. D. Howell, M. W. Taylor, P. J. Clark, N. Afdhal, and H. R. Rosen. 2011. Natural killer inhibitory receptor expression associated with treatment failure and interleukin-28B genotype in patients with chronic hepatitis C. Hepatology 54: 1559-1569.   DOI
38 Amadei, B., S. Urbani, A. Cazaly, P. Fisicaro, A. Zerbini, P. Ahmed, G. Missale, C. Ferrari, and S. I. Khakoo. 2010. Activation of natural killer cells during acute infection with hepatitis C virus. Gastroenterology 138: 1536-1545.   DOI
39 Pelletier, S., C. Drouin, N. Bedard, S. I. Khakoo, J. Bruneau, and N. H. Shoukry. 2010. Increased degranulation of natural killer cells during acute HCV correlates with the magnitude of virus-specific T cell responses. J. Hepatol. 53: 805-816.   DOI
40 Werner, J. M., T. Heller, A. M. Gordon, A. Sheets, A. H. Sherker, E. Kessler, K. S. Bean, M. Stevens, J. Schmitt, and B. Rehermann. 2013. Innate immune responses in hepatitis C virus exposed healthcare workers who do not develop acute infection. Hepatology in press : http://onlinelibrary. wiley.com/doi/10.1002/hep.26353/abstract
41 Ahlenstiel, G., R. H. Titerence, C. Koh, B. Edlich, J. J. Feld, Y. Rotman, M. G. Ghany, J. H. Hoofnagle, T. J. Liang, T. Heller, and B. Rehermann. 2010. Natural killer cells are polarized toward cytotoxicity in chronic hepatitis C in an interferon- alfa-dependent manner. Gastroenterology 138: 325-335.   DOI
42 Edlich, B., G. Ahlenstiel, A. Z. Azpiroz, J. Stoltzfus, M. Noureddin, E. Serti, J. J. Feld, T. J. Liang, Y. Rotman, and B. Rehermann. 2012. Early changes in interferon signaling define natural killer cell response and refractoriness to interferon- based therapy of hepatitis C patients. Hepatology 55:39-48.   DOI
43 Miyagi, T., M. P. Gil, X. Wang, J. Louten, W. M. Chu, and C. A. Biron. 2007. High basal STAT4 balanced by STAT1 induction to control type 1 interferon effects in natural killer cells. J. Exp. Med. 204: 2383-2396.   DOI
44 Miyagi, T., T. Takehara, K. Nishio, S. Shimizu, K. Kohga, W. Li, T. Tatsumi, N. Hiramatsu, T. Kanto, and N. Hayashi. 2010. Altered interferon-alpha-signaling in natural killer cells from patients with chronic hepatitis C virus infection. J. Hepatol. 53: 424-430.   DOI
45 Varchetta, S., D. Mele, S. Mantovani, B. Oliviero, E. Cremonesi, S. Ludovisi, G. Michelone, M. Alessiani, R. Rosati, M. Montorsi, and M. U. Mondelli. 2012. Impaired intrahepatic natural killer cell cytotoxic function in chronic hepatitis C virus infection. Hepatology 56: 841-849.   DOI
46 Kramer, B., C. Korner, M. Kebschull, A. Glassner, M. Eisenhardt, H. D. Nischalke, M. Alexander, T. Sauerbruch, U. Spengler, and J. Nattermann. 2012. 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: 1201-1213.
47 Biron, C. A., K. B. Nguyen, G. C. Pien, L. P. Cousens, and T. P. Salazar-Mather. 1999. Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu. Rev. Immunol. 17: 189-220.   DOI
48 Pembroke, T., A. Christian, E. Jones, R. K. Hills, E. C. Wang, A. M. Gallimore, and A. Godkin. 2013. The paradox of NKp46＋ natural killer cells: drivers of severe hepatitis C virus- induced pathology but in-vivo resistance to interferon alpha treatment. Gut. in press: http://gut.bmj.com/content/ early/2013/05/10/gutjnl-2013-304472.
49 Golden-Mason, L., A. E. Stone, K. M. Bambha, L. Cheng, and H. R. Rosen. 2012. Race- and gender-related variation in natural killer p46 expression associated with differential anti- hepatitis C virus immunity. Hepatology 56: 1214-1222.
50 Eisenhardt, M., A. Glassner, B. Kramer, C. Korner, B. Sibbing, P. Kokordelis, H. D. Nischalke, T. Sauerbruch, U. Spengler, and J. Nattermann. 2012. The CXCR3(＋)CD56Bright phenotype characterizes a distinct NK cell subset with anti-fibrotic potential that shows dys-regulated activity in hepatitis C. PLoS. One 7: e38846.   DOI
51 Kaser, A., B. Enrich, O. Ludwiczek, W. Vogel, and H. Tilg. 1999. Interferon-alpha (IFN-alpha) enhances cytotoxicity in healthy volunteers and chronic hepatitis C infection mainly by the perforin pathway. Clin. Exp. Immunol.118: 71-77.   DOI
52 Bozzano, F., A. Picciotto, P. Costa, F. Marras, V. Fazio, I. Hirsch, D. Olive, L. Moretta, and A. De Maria. 2011. Activating NK cell receptor expression/function (NKp30, NKp46, DNAM-1) during chronic viraemic HCV infection is associated with the outcome of combined treatment. Eur. J. Immunol. 41: 2905-2914.   DOI
53 Oliviero, B., D. Mele, E. Degasperi, A. Aghemo, E. Cremonesi, M. G. Rumi, C. Tinelli, S. Varchetta, S. Mantovani, M. Colombo, and M. U. Mondelli. 2013. Natural killer cell dynamic profile is associated with treatment outcome in patients with chronic HCV infection. J. Hepatol. 59: 38-44.   DOI
54 Conry, S. J., Q. Meng, G. Hardy, N. L. Yonkers, J. M. Sugalski, A. Hirsch, P. Davitkov, A. Compan, Y. Falck-Ytter, R. E. Blanton, B. Rodriguez, C. V. Harding, and D. D. Anthony. 2012. Genetically associated CD16(＋)56(-) natural killer cell interferon (IFN)-$\alpha$R expression regulates signaling and is implicated in IFN-$\alpha$-induced hepatitis C virus decline. J. Infect. Dis. 205: 1131-1141.   DOI
55 Ahlenstiel, G., B. Edlich, L. J. Hogdal, Y. Rotman, M. Noureddin, J. J. Feld, L. E. Holz, R. H. Titerence, T. J. Liang, and B. Rehermann. 2011. Early changes in natural killer cell function indicate virologic response to interferon therapy for hepatitis C. Gastroenterology 141: 1231-1239.   DOI
56 Lagging, M., A. I. Romero, J. Westin, G. Norkrans, A. P. Dhillon, J. M. Pawlotsky, S. Zeuzem, M. von Wagner, F. Negro, S. W. Schalm, B. L. Haagmans, C. Ferrari, G. Missale, A. U. Neumann, E. Verheij-Hart, and K. Hellstrand. 2006. IP-10 predicts viral response and therapeutic outcome in difficult- to-treat patients with HCV genotype 1 infection. Hepatology 44: 1617-1625.   DOI
57 Dring, M. M., M. H. Morrison, B. P. McSharry, K. J. Guinan, R. Hagan, C. O'Farrelly, and C. M. Gardiner. 2011. Innate immune genes synergize to predict increased risk of chronic disease in hepatitis C virus infection. Proc. Natl. Acad. Sci. USA 108: 5736-5741.   DOI
58 Kramer, B., M. Eisenhardt, A. Glassner, C. Korner, T. Sauerbruch, U. Spengler, and J. Nattermann. 2011. Do lambda- IFNs IL28A and IL28B act on human natural killer cells? Proc. Natl. Acad. Sci. USA 108: E519-520   DOI
59 Stegmann, K. A., N. K. Bjorkstrom, H. Liermann, S. Ciesek, P. Riese, J. Wiegand, J. Hadem, P. V. Suneetha, J. Jaroszewicz, C. Wang, V. Schlaphoff, P. Fytili, M. Cornberg, M. P. Manns, R. Geffers, T. Pietschmann, C. A. Guzman, H. G. Ljunggren, and H. Wedemeyer. 2010. Interferon alpha induces TRAIL on natural killer cells is associated with control of hepatitis C virus infection. Gastroenterology 138: 1885- 1897.   DOI
60 O'Connor, K. S., G. Ahlenstiel, V. Suppiah, S. Schibeci, A. Ong, R. Leung, D . van der Poorten, M. W. Douglas, M. D. Weltman, G. J. Stewart, C. Liddle, J. George, and D. R. Booth. 2013. IFNL3 mediates interaction between innate immune cells: Implications for hepatitis C virus pathogenesis. Innate. Immun. in press: http://ini.sagepub.com/content/ early/2013/09/13/1753425913503385.
61 Gane, E. J., B. C. Portmann, N. V. Naoumov, H. M. Smith, J. A. Underhill, P. T. Donaldson, G. Maertens, and R. Williams. 1996. Long-term outcome of hepatitis C infection after liver transplantation. N. Engl. J. Med. 334: 815-820.   DOI
62 Feray, C., L. Caccamo, G. J. Alexander, B. Ducot, J. Gugenheim, T. Casanovas, C. Loinaz, M. Gigou, P. Burra, L. Barkholt, R. Esteban, T. Bizollon, J. Lerut, A. Minello-Franza, P. H. Bernard, K. Nachbaur, D. Botta- Fridlund, H. Bismuth, S. W. Schalm, and D. Samuel. 1999. European collaborative study on factors influencing outcome after liver transplantation for hepatitis C. European Concerted Action on Viral Hepatitis (EUROHEP) Group. Gastroenterology 117: 619-625.   DOI
63 de Arias, A. E., S. E. Haworth, L. S. Belli, P. Burra, G. Pinzello, M. Vangeli, E. Minola, M. Guido, P. Boccagni, T. M. De Feo, R. Torelli, M. Cardillo, M. Scalamogna, and F. Poli. 2009. Killer cell immunoglobulin-like receptor genotype and killer cell immunoglobulin-like receptor-human leukocyte antigen C ligand compatibility affect the severity of hepatitis C virus recurrence after liver transplantation. Liver Transpl. 15: 390-399.   DOI
64 Trinchieri, G. 1989. Biology of natural killer cells. Adv. Immunol. 47: 187-376.   DOI
65 Legaz, I., M. R. Lopez-Alvarez, J. A. Campillo, M. R. Moya-Quiles, J. M. Bolarin, J. de la Pena, G. Salgado, L. Gimeno, A. M. Garcia-Alonso, M. Muro, M. Miras, C. Alonso, M. R. Alvarez-Lopez, and A. Minguela. 2013. KIR gene mismatching and KIR/C ligands in liver transplantation: consequences for short-term liver allograft injury. Transplantation 95: 1037-1044.   DOI
66 Moya-Quiles, M. R., R. Alvarez, M. Miras, J. Gomez-Mateo, M. R. Lopez-Alvarez, I. Marin-Moreno, E. Martinez-Barba, M. P. Sanchez-Mozo, M. Gomez, F. Arnal, F. Sanchez-Bueno, L. A. Marin, A. M. Garcia-Alonso, A. Minguela, M. Muro, P. Parrilla, C. Alonso, and M. R. Alvarez-Lopez. 2007. Impact of recipient HLA-C in liver transplant: a protective effect of HLA-Cw*07on acute rejection. Hum. Immunol. 68: 51-58.   DOI
67 Varchetta, S., B. Oliviero, M. Francesca Donato, F. Agnelli, C. Rigamonti, E. Paudice, E. Arosio, M. Berra, G. Rossi, C. Tinelli, F. F. Fagnoni, M. Colombo, D. Mavilio, and M. U. Mondelli. 2009. Prospective study of natural killer cell phenotype in recurrent hepatitis C virus infection following liver transplantation. J. Hepatol. 50: 314-322.
68 Lopez-Vazquez, A., L. Rodrigo, J. Martinez-Borra, R. Perez, M. Rodriguez, J. L. Fdez-Morera, D. Fuentes, S. Rodriguez- Rodero, S. Gonzaez, and C. Lopez-Larrea. 2005. Protective effect of the HLA-Bw4I80 epitope and the killer cell immunoglobulin- like receptor 3DS1 gene against the development of hepatocellular carcinoma in patients with hepatitis C virus infection. J. Infect. Dis. 192: 162-165.   DOI
69 Yuen, M. F. and S. Norris. 2001. Expression of inhibitory receptors in natural killer (CD3(-)CD56(＋)) cells and CD3(＋)CD56(＋) cells in the peripheral blood lymphocytes and tumor infiltrating lymphocytes in patients with primary hepatocellular carcinoma. Clin. Immunol. 101: 264-269.   DOI
70 WHO. Hepatitis C. Fact Sheet No. 164. Updated July 2013. http://www.who.int/mediacentre/factsheets/fs164/en/.
71 Hoofnagle, J. H. 2002. Course and outcome of hepatitis C. Hepatology 36: S21-29.
72 Burra, P. 2009. Hepatitis C. Semin. Liver Dis. 29: 53-65.   DOI
73 NIH office of the director. 2002. NIH consensus statement on management of hepatitis C. NIH Consens. State. Sci. Statements 19: 1-46.
74 Feld, J. J. and J. H. Hoofnagle. 2005. Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature 436: 967-972.   DOI
75 Moretta, L., C. Bottino, D. Pende, M. C. Mingari, R. Biassoni, and A. Moretta. 2002. Human natural killer cells: their origin, receptors and function. Eur .J. Immunol. 32: 1205-1211.   DOI
76 Jacobson, I. M., J. G. McHutchison, G. Dusheiko, A. M. Di Bisceglie, K. R. Reddy, N. H. Bzowej, P. Marcellin, A. J. Muir, P. Ferenci, R. Flisiak, J. George, M. Rizzetto, D. Shouval, R. Sola, R. A. Terg, E. M. Yoshida, N. Adda, L. Bengtsson, A. J. Sankoh, T. L. Kieffer, S. George, R. S. Kauffman, and S. Zeuzem. 2011. Telaprevir for previously untreated chronic hepatitis C virus infection. N. Engl. J. Med. 364: 2405-2416.   DOI
77 Poordad, F., J. McCone, Jr., B. R. Bacon, S. Bruno, M. P. Manns, M. S. Sulkowski, I. M. Jacobson, K. R. Reddy, Z. D. Goodman, N. Boparai, M. J. DiNubile, V. Sniukiene, C. A. Brass, J. K. Albrecht, and J. P. Bronowicki. 2011. Boceprevir for untreated chronic HCV genotype 1 infection. N. Engl. J. Med. 364: 1195-1206.   DOI
78 Lee, S. H., T. Miyagi, and C. A. Biron. 2007. Keeping NK cells in highly regulated antiviral warfare. Trends Immunol. 28: 252-259.   DOI
79 Hu, P. F., L. E. Hultin, P. Hultin, M. A. Hausner, K. Hirji, A. Jewett, B. Bonavida, R. Detels, and J. V. Giorgi. 1995. Natural killer cell immunodeficiency in HIV disease is manifest by profoundly decreased numbers of CD16＋CD56＋ cells and expansion of a population of CD16dimCD56- cells with low lytic activity. J. Acquir Immune Defic. Syndr. Hum. Retrovirol.10: 331-440.
80 Mavilio, D., G. Lombardo, J. Benjamin, D. Kim, D. Follman, E. Marcenaro, M. A. O'Shea, A. Kinter, C. Kovacs, A. Moretta, and A. S. Fauci. 2005 Characterization of CD56-/CD16＋ natural killer (NK) cells: a highly dysfunctional NK subset expanded in HIV-infected viremic individuals. Proc. Natl. Acad. Sci. USA 102: 2886-2891.   DOI