Natural Killer Cells in HCV Infection
Journal of Clinical and Cellular Immunology

Journal of Clinical and Cellular Immunology
Open Access

ISSN: 2155-9899

+44 1223 790975

Short Communication - (2017) Volume 8, Issue 6

Natural Killer Cells in HCV Infection

Lu Long1 and Tao Shen2*
1Department of Laboratory Medicine, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
2Department of Microbiology and Center of Infectious Diseases, School of Basic Medical Sciences, Peking University, Beijing, China
*Corresponding Author: Tao Shen, Department of Microbiology and Center of Infectious Diseases, School of Basic Medical Sciences, Peking University, Beijing, China, Tel: 86-10-82805070 Email:


Natural killer (NK) cells play a vital role in controlling viral infection. This commentary will introduce the alteration of NK cells in different infected status involving frequencies, phenotypes and functions. Moreover, it highlights the function of antibody-dependent cell-mediated cytotoxicity (ADCC) in HCV and other virus infection, and concerns its role in vaccine development and immunotherapies

Keywords: Natural killer cell; Hepatitis virus C; ADCC


Hepatitis virus C (HCV) infection is a main cause of viral hepatitis, liver cirrhosis and hepatocellular carcinoma [1]. Nearly 3% of world population are infected with HCV [1], and about half million people die from cirrhosis, hepatocellular carcinoma or other diseases caused by HCV infection each year [2]. Therapies for HCV infection include interferon (IFN) α combined with ribavirin (RBV) [3], direct-acting antivirals (DAAs) [4] and host-targeting agents (HTA) [5]. Especially, DAAs therapy, a combination of Sofosbuvir and Ledipasvir with or without ribavirin, improves the sustained virological response (SVR) up to 98~99% [6].

NK cells are major effector cells of innate immunity, directly killing pathogen-infected cells and tumor cells [7]. According to CD56 and CD16 expression, NK cells can be divided into three subsets: CD56briCD16dim/neg(~10%), CD56dimCD16+(~90%) and CD56negCD16+[8,9]. CD56briCD16dim/neg subset produces cytokines such as IFNγ [10], CD56dimCD16+subset presents high cytotoxicity but little cytokine secretion [11], and CD56negCD16+ subset has been shown functionally deficient and is increased in chronic HIV and HCV infection [12]. Activation of NK cells is determined by the balance between signals mediated by activating receptor and inhibitory receptor, while prior sensitization is not necessary. Inhibitory receptors expressed on NK cells can trigger inhibitory signal transduction by recognizing major histocompatibility complex (MHC) class I molecules, such as killer cell immunoglobulin-like receptors (KIRs) and CD94/NKG2A heterodimers [13-15]. Activating receptors consist of lectin-like receptors NKG2D, NKG2C [16], and natural cytotoxicity receptors (NCRs) [17], including NKp30, NKp44, and NKp46. NKG2D recognizes MHC class I chain-related protein (MIC) A, B and UL16- binding proteins (ULBPs) [18,19]. NK cells also express FCγR III (CD16), which can bind to Fc portion of immunoglobulins to trigger antibody-dependent cell-mediated cytotoxicity (ADCC) [20,21]. Following cross-linking between CD16 and Fc portion, the C-terminal ITAM will be phosphorylated to activate Ca2+-dependent signaling pathway, leading to release of granzyme B and perforin and secretion of several antiviral cytokines and chemokines, which eventually results in DNA fragmentation and apoptosis of the target cells [22-24].

NK Cells And HCV Infection

NK cells are accounted for 5%~20% of peripheral blood mononuclear cells and comprise 30%~50% of liver-resident lymphocytes [25]. NK cells play an important role during HCV infection. In acute hepatitis C, a reduced frequency of CD56dim subset and an increased proportion of CD56bri subset are reported [26-28]. Receptors expressed on NK cell surface are also altered, with lower frequencies of NKp30, NKp46, CD161 and NKG2D on NK cells after acute infection [27]. Amadei et al. suggest an increase of NKG2DNK cells irrespective of outcome, and cytotoxicity of NK cells is increased only in individuals with KIRs combined with HLA-C1, especially in self-limited individuals [26]. Pavloset et al. demonstrate that elevated frequencies of NKG2D and NKp46 on NK cells may be related to selflimited HCV infection [29]. Werner et al. describe a strong NK cell response in healthcare workers with low-level HCV exposure but do not develop into acute HCV infection [30]. Notably, Pelletier et al. find an increased NK cell degranulation in early phase of HCV infection in a cohort of intravenous (IV) drug users who cleared HCV spontaneously [31]. Peter et al. [32] also suggest that sustained NK cell activation protected highly-exposed uninfected injecting drug users from HCV infection. In chronic HCV infection, the distribution and phenotype of NK cell subsets are also changed [33,34]. The frequency of CD56dimCD16+subset is decreased and the proportion of CD56- CD16+ subset with defective function is elevated in chronic HCV infection [12,35,36]. Some controversies are existed in the expression of NCRs. One study shows that the levels of NKp46 and NKp30 expressed on NK cell surface are significantly decreased in chronic HCV infected subjects [37], while another study displays an increased proportion of NKp44, NKp46 and NKp30 [38]. Furthermore, HCV non-structural proteins 5A(NS5A) can induce secretion of IL-10 by monocytes to promote production of transforming growth factor (TGF) β, resulting to lower surface expression of NKG2D which plays an important role in the control of HCV infection [39]. Several researchers report that the function of NK cells appears to be polarized during development of chronic HCV infection. Cytotoxicity of NK cell is up-regulated while IFN-γ production by NK cells is down-regulated [33,36,38]. This functional polarization of NK cells may contribute to persistence of HCV virus and increased liver damages [38]. NKp46highNK cells are enriched in liver and exert stronger cytotoxicity against hepatic stellate cells (HSCs) [38,40]. Glässneret et al. demonstrate that NK cells from HCV-infected patients can induce apoptosis of activated HSCs, and perform an anti-fibrotic role in chronic hepatitis C [41]. Taken together, NK cells play a pivotal role in the control of HCV infection despite of some discrepancies existing in some studies.

Fewer studies have been done on the ADCC activity mediated by NK cell in HCV infection. It is demonstrated that spontaneous clearance of HCV occurs most often after the induction of an anti- HCV humoral immune response [42,43], indicating that antibodymediated immune responses, such as NK-ADCC, may contribute to the spontaneous clearance of HCV. Jacob et al. demonstrate that specific antibodies to HCV E2 in serum can mediate ADCC activity, while the pathological mechanisms have not yet been studied in chronic HCV infection [44]. Alter et al. stimulate NK cells with the P815-Ab antigen-antibody complex, and find that the proportion of IFN-γ-producing NK cells and CD107a-positive NK cells is lower in chronic HCV infected individuals than in subjects with spontaneous recovery from HCV infection [27]. Barbara et al. report an impaired antibody-dependent cytotoxicity induced by metzincin-mediated CD16 cleavage due to hepatitis C virus-induced NK cell activation [45]. Our research also reveals a dysfunctional characteristic of antibody-dependent NK cell responses in chronic HCV carriers [28]. Our study reveals that non-neutralizing epitopes can induce robust hepatitis C virus (HCV)-specific antibody-dependent CD56+ NK cell responses in chronic HCV-infected patients [28]. Of note, ADCC activity in cancer immunotherapies and protective immune responses in several virus infections is becoming more and more important. ADCC is utilized in the treatment of various cancers that involve tumor-antigens targeting by monoclonal antibodies (mAbs), such as Rituximab for non-Hodgkin’s lymphoma [46] and Obinutuzumab for chronic lymphocytic leukemia [47].


Nowadays, more and more studies turn to focus on induction of ADCC-mediating Abs during vaccine research and development [48-50]. ADCC displays a remarkable role in protecting against HIV infection in the RV144 Thai trial for HIV vaccine, resulting to an approximately 31% protection [48]. ADCC response is also used in universal influenza vaccines, since ADCC-mediating Abs can target more conserved regions of influenza virus and recognize a broader array of influenza strains [51]. It is anticipated that the strategies of inducing ADCC-mediating Abs may be used broadly in vaccine development and immunotherapies.


This work was financially supported by the National Science and Technology Major Project of China (2017ZX10202101-003, 2017ZX10301101-001, and 2017ZX09309008-003).


  1. Lavanchy D (2009) The global burden of hepatitis C. Liver Int Suppl 1: 74-81.
  2. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, et al. (2012) Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380: 2095-2128.
  3. NIH Consensus Statement on Management of Hepatitis C (2002) NIH Consens State Sci Statements 19: 1-46.
  4. Lok AS, Gardiner DF, Lawitz E, Martorell C, Everson GT, et al. (2012) Preliminary study of two antiviral agents for hepatitis C genotype . N Engl J Med 366: 216-224.
  5. Baugh JM, Garcia-Rivera JA, Gallay PA (2013) Host-targeting agents in the treatment of hepatitis C: a beginning and an end? Antiviral Res 100: 555-561.
  6. Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, et al. (2014) Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 370: 1889-1898.
  7. Vivier E, Ugolini S, Blaise D, Chabannon C, Brossay L (2012) Targeting natural killer cells and natural killer T cells in cancer. Nat Rev Immunol 12: 239-252.
  8. Cheent K, Khakoo SI (2011) Natural killer cells and hepatitis C: action and reaction. Gut 60: 268-278.
  9. Gonzalez VD, Falconer K, Bjorkstrom NK, Blom KG, Weiland O, et al. (2009) 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 183: 6612-6618.
  10. Cooper MA, Fehniger TA, Turner SC, Chen KS, Ghaheri BA, et al. (2001) Human natural killer cells: a unique innate immunoregulatory role for the CD56 (bright) subset. Blood 10: 3146-3151.
  11. Korbel DS, Norman PJ, Newman KC, Horowitz A, Gendzekhadze K, et al. (2009) Killer Ig-like receptor (KIR) genotype predicts the capacity of human KIR-positive CD56dim NK cells to respond to pathogen-associated signals. J Immunol 182: 6426-6434.
  12. Björkström NK, Ljunggren HG, Sandberg JK (2010) CD56 negative NK cells: origin, function, and role in chronic viral disease. Trends Immunol 31: 401-406.
  13. Seidel E, Glasner A, Mandelboim O (2012) Virus-mediated inhibition of natural cytotoxicity receptor recognition. Cell Mol Life Sci 69: 3911-3920.
  14. Moretta L, Moretta A (2004) Unravelling natural killer cell function: triggering and inhibitory human NK receptors. EMBO J 23: 255-259.
  15. Joyce MG, Sun PD (2011) The structural basis of ligand recognition by natural killer cell receptors. J Biomed Biotechnol 2011: 203-628.
  16. Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, et al. (2011) Innate or adaptive immunity? The example of natural killer cells. Science 331: 44-49.
  17. Moretta L, Bottino C, Pende D, Castriconi R, Mingari MC, et al. (2006) Surface NK receptors and their ligands on tumor cells. Semin Immunol 18: 151-158.
  18. Obeidy P, Sharland AF (2009) NKG2D and its ligands. Int J Biochem Cell Biol 41: 2364-2367.
  19. Niwa R, Natsume A, Uehara A, Wakitani M, Iida S, et al. (2005) IgG subclass-independent improvement of antibody-dependent cellular cytotoxicity by fucose removal from Asn297-linked oligosaccharides. J Immunol Methods 306: 151-160.
  20. Trinchieri G, Valiante N (1993) Receptors for the Fc fragment of IgG on natural killer cells. Nat Immun 12: 218-234.
  21. Seidel UJ, Schlegel P, Lang P (2013) Natural killer cell mediated antibody-dependent cellular cytotoxicity in tumor immunotherapy with therapeutic antibodies. Front Immunol 4: 76.
  22. Oliva A, Kinter AL, Vaccarezza M, Rubbert A, Catanzaro A, et al. (1998) Natural killer cells from human immunodeficiency virus (HIV)-infected individuals are an important source of CC-chemokines and suppress HIV-1 entry and replication in vitro. J Clin Invest 102: 223-231.
  23. Stratov I, Chung A, Kent SJ (2008) Robust NK cell-mediated human immunodeficiency virus (HIV)-specific antibody-dependent responses in HIV-infected subjects. J Virol 82: 5450-5459.
  24. Doherty DG, O'Farrelly C (2000) Innate and adaptive lymphoid cells in the human liver. Immunol Rev 174: 5-20.
  25. Amadei B, Urbani S, Cazaly A, Fisicaro P, Zerbini A, et al. (2010) Activation of natural killer cells during acute infection with hepatitis C virus. Gastroenterology 138: 1536-1545.
  26. Alter G, Jost S, Rihn S, Reyor LL, Nolan BE, et al. (2011) Reduced frequencies of NKp30+NKp46+, CD161+, and NKG2D+ NK cells in acute HCV infection may predict viral clearance. J Hepatol 55: 278-288.
  27. Long L, Jia M, Fan X, Liang H (2017) Non-neutralizing epitopes induce robust hepatitis C virus (HCV)-specific antibody-dependent CD56+ natural killer cell responses in chronic HCV-infected patients. Clin Exp Immunol 189: 92-102.
  28. Kokordelis P, Kramer B, Korner C, Boesecke C, Voigt E, et al. (2014) An effective interferon-gamma-mediated inhibition of hepatitis C virus replication by natural killer cells is associated with spontaneous clearance of acute hepatitis C in human immunodeficiency virus-positive patients. Hepatology 59: 814-827.
  29. Werner JM, Heller T, Gordon AM, Sheets A, Sherker AH, et al. (2013) Innate immune responses in hepatitis C virus-exposed healthcare workers who do not develop acute infection. Hepatology 58: 1621-1631.
  30. Pelletier S, Drouin C, Bedard N, Khakoo SI, Bruneau J, et al. (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.
  31. Sugden PB, Cameron B, Mina M, Lloyd AR, investigators H (2014) Protection against hepatitis C infection via NK cells in highly-exposed uninfected injecting drug users. J Hepatol 61: 738-745.
  32. Oliviero B, Varchetta S, Paudice E, Michelone G, Zaramella M, et al. (2009) Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections. Gastroenterology 137: 1151-1160.
  33. Pembroke T, Christian A, Jones E, Hills RK, Wang EC, et al. (2014) The paradox of NKp46+ natural killer cells: drivers of severe hepatitis C virus-induced pathology but in-vivo resistance to interferon alpha treatment. Gut 63: 515-524.
  34. Morishima C, Paschal DM, Wang CC, Yoshihara CS, Wood BL, et al. (2006) Decreased NK cell frequency in chronic hepatitis C does not affect ex vivo cytolytic killing. Hepatology 43: 573-580.
  35. Dessouki O, Kamiya Y, Nagahama H, Tanaka M, Suzu S, et al. (2010) Chronic hepatitis C viral infection reduces NK cell frequency and suppresses cytokine secretion: Reversion by anti-viral treatment. Biochem Biophys Res Commun 393: 331-337.
  36. Nattermann J, Feldmann G, Ahlenstiel G, Langhans B, Sauerbruch T, et al. (2006) Surface expression and cytolytic function of natural killer cell receptors is altered in chronic hepatitis C. Gut 55: 869-877.
  37. Ahlenstiel G, Titerence RH, Koh C, Edlich B, Feld JJ, et al. (2010) Natural killer cells are polarized toward cytotoxicity in chronic hepatitis C in an interferon-alfa-dependent manner. Gastroenterology 138: 325-335.
  38. Sène D, Levasseur F, Abel M, Lambert M, Camous X, et al. (2010) Hepatitis C virus (HCV) evades NKG2D-dependent NK cell responses through NS5A-mediated imbalance of inflammatory cytokines. PLoS Pathog 6: e1001184.
  39. Kramer B, Korner C, Kebschull M, Glassner A, Eisenhardt M, et al. (2012) Natural killer p46 High 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.
  40. Glassner A, Eisenhardt M, Kramer B, Korner C, Coenen M, et al. (2012) NK cells from HCV-infected patients effectively induce apoptosis of activated primary human hepatic stellate cells in a TRAIL-, FasL- and NKG2D-dependent manner. Lab Invest 92: 967-977.
  41. Grebely J, Page K, Sacks-Davis R, Loeff MS, Rice TM, et al. (2014) The effects of female sex, viral genotype, and IL28B genotype on spontaneous clearance of acute hepatitis C virus infection. Hepatology 59: 109-120.
  42. Park SH, Rehermann B (2014) Immune responses to HCV and other hepatitis viruses. Immunity 40: 13-24.
  43. Nattermann J, Schneiders AM, Leifeld L, Langhans B, Schulz M, et al. (2005) Serum antibodies against the hepatitis C virus E2 protein mediate antibody-dependent cellular cytotoxicity (ADCC). J Hepatol 42: 499-504.
  44. Oliviero B, Mantovani S, Varchetta S, Mele D, Grossi G, et al. (2017) Hepatitis C virus-induced NK cell activation causes metzincin-mediated CD16 cleavage and impaired antibody-dependent cytotoxicity. J Hepatol 66: 1130-1137.
  45. Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, et al. (2002) Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 99: 754-758.
  46. Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, et al. (2014) Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 370: 1101-1110.
  47. McElrath MJ, Haynes BF (2010) Induction of immunity to human immunodeficiency virus type-1 by vaccination. Immunity 33: 542-554.
  48. Srivastava V, Yang Z, Hung IF, Xu J, Zheng B, et al. (2013) Identification of dominant antibody-dependent cell-mediated cytotoxicity epitopes on the hemagglutinin antigen of pandemic H1N1 influenza virus. J Virol 87: 5831-5840.
  49. Gorander S, Ekblad M, Bergstrom T, Liljeqvist JA (2014) Anti-glycoprotein g antibodies of herpes simplex virus 2 contribute to complete protection after vaccination in mice and induce antibody-dependent cellular cytotoxicity and complement-mediated cytolysis. Viruses 6: 4358-4372.
  50. Jegaskanda S, Reading PC, Kent SJ (2014) Influenza-specific antibody-dependent cellular cytotoxicity: toward a universal influenza vaccine. J Immunol 193: 469-475.
Citation: Long L, Shen T (2017) Natural Killer Cells in HCV Infection. J Clin Cell Immunol 8: 530.

Copyright: ©2017 Long L, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.