Direct antiviral agents (DAAs) can eliminate hepatitis C virus rapidly and make chronic hepatitis C (CHC) curable. The changes in the innate immune system during treatment with DAAs are still in dispute. To investigate how the functions of natural killer (NK) cells change during and after treatment with DAAs in each NK cell subset. Thirteen CHC patients were treated with sofosbuvir/ledipasvir, and the expression levels of NKp46 and NKG2A were tested via flow cytometry at baseline, at 2, 4, 8 and 12 weeks during the therapy and 12 and 24 weeks after the end of treatment; expression levels were compared between CHC patients and 13 healthy controls. A redirected killing assay was used to detect the cytotoxicity of NK cells. After coculturing NK cells with JFH-Huh7 cells for 72 h, HCV RNA was tested to analyze the inhibition ability of NK cells. All patients achieved sustained virologic response. The expression of the activating receptor NKp46 was decreased first at week 8 during therapy with DAAs and then increased and normalized to levels in healthy controls after treatment with DAAs. The expression of the inhibitory receptor NKG2A was decreased during and after treatment with DAAs. Each NK cell subset has a similar changing trend during and after treatment with DAAs, although some differences can be found earlier and later. The ratio of NKp46 and NKG2A was upregulated after treatment with DAAs. CD56bright NK cells have less amplitude in the frequency ratio changes after treatment with DAAs. The coculture results showed that both the specific lysis and the inhibition of HCV replication were significantly upregulated after treatment with DAAs. DAA treatments can affect patients’ NK cell function. After DAA treatments, the expression of functional markers is downregulated, but the potential activity of NK cells is upregulated. The function of NK cells is normalized to levels in healthy controls. CD56bright NK cells play an important role in this process.
Direct antiviral agents Hepatitis C virus Innate immune system Natural killer cells Function
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This study was supported by the National S&T Major Projects for Infectious Diseases Control (2017ZX10302201-004-001 and 2017ZX10203202-003-003).
Compliance with ethical standards
Conflicts of interest
There were no conflicts of interest in this study.
Lodoen MB, Lanier LL. Natural killer cells as an initial defense against pathogens. Curr Opin Immunol. 2006;18:391–8.CrossRefGoogle Scholar
Yoon JC, Yang CM, Song Y, Lee JM. Natural killer cells in hepatitis C: current progress. World J Gastroenterol. 2016;22:1449–60.CrossRefGoogle Scholar
Lee SH, Miyagi T, Biron CA. Keeping NK cells in highly regulated antiviral warfare. Trends Immunol. 2007;28:252–9.CrossRefGoogle Scholar
Björkström NK, Ljunggren H-G, Sandberg JK. CD56 negative NK cells: origin, function, and role in chronic viral disease. Trends Immunol. 2010;31:401–6.CrossRefGoogle Scholar
Spaan M, van Oord G, Kreefft K, et al. Immunological analysis during interferon-free therapy for chronic hepatitis C virus infection reveals modulation of the natural killer cell compartment. J Infect Dis. 2016;213:216–23.CrossRefGoogle Scholar
Vidal SM, Khakoo SI, Biron CA. Natural killer cell responses during viral infections: flexibility and conditioning of innate immunity by experience. Curr Opin Virol. 2011;1:497–512.CrossRefGoogle Scholar
de Groen RA, Boltjes A, Hou J, et al. IFNλ-mediated IL-12 production in macrophages induces IFNγ production in human NK cells. Eur J Immunol. 2014;45:250–9.CrossRefGoogle Scholar
Ahlenstiel G, Titerence RH, Koh C, Edlich B, et al. Natural killer cells are polarized toward cytotoxicity in chronic hepatitis C in an interferon-alfa-dependent manner. Gastroenterology. 2010;138:325–35.CrossRefGoogle Scholar
Oliviero B, Varchetta S, Paudice E, et al. Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections. Gastroenterology. 2009;137:1151–60.CrossRefGoogle Scholar
De Maria A, Fogli M, Mazza S, et al. Increased natural cytotoxicity receptor expression and relevant IL-10 production in NK cells from chronically infected viremic HCV patients. Eur J Immunol. 2007;37:445–55.CrossRefGoogle Scholar
Sène D, Levasseur F, Abel M, et al. Hepatitis C virus (HCV) evades NKG2Ddependent NK cell responses through NS5A-mediated imbalance of inflammatory cytokines. PLoS Pathog. 2010;6:e1001184.CrossRefGoogle Scholar
Golden-Mason L, Madrigal-Estebas L, McGrath E, et al. Altered natural killer cell subset distributions in resolved and persistent hepatitis C virus infection following single source exposure. Gut. 2008;57:1121–8.CrossRefGoogle Scholar
Nattermann J, Feldmann G, Ahlenstiel G, Langhans B, Sauerbruch T, Spengler U. Surface expression and cytolytic function of natural killer cell receptors is altered in chronic hepatitis C. Gut. 2006;55:869–77.CrossRefGoogle Scholar
Krämer B, Körner C, Kebschull M, et al. Natural killer p46High expression defines a natural killer cell subset that is potentially involved in control of hepatitis C virus replication and modulation of liver fibrosis. Hepatology. 2012;56:1201–13.CrossRefGoogle Scholar
Serti E, Chepa-Lotrea X, Kim YJ, et al. Successful interferon free therapy of chronic hepatitis C virus infection normalizes natural killer cell function. Gastroenterology. 2015;149:190–200.CrossRefGoogle Scholar
Stanaway JD, Flaxman AD, Naghavi M, et al. The global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013. Lancet. 2016;388:1081–8.CrossRefGoogle Scholar
Collins JM, Raphael KL, Terry C, et al. Hepatitis B virus reactivation during successful treatment of hepatitis C virus with sofosbuvir and simeprevir. Clin Infect Dis. 2015;61:1304–6.CrossRefGoogle Scholar
Ende AR, Kim NH, Yeh MM, Harper J, Landis CS. Fulminant hepatitis B reactivation leading to liver transplantation in a patient with chronic hepatitis C treated with simeprevir and sofosbuvir: a case report. J Med Case Rep. 2015;9:164.CrossRefGoogle Scholar
Takayama H, Sato T, Ikeda F, Fujiki S. Reactivation of hepatitis B virus during interferon-free therapy with daclatasvir and asunaprevir in patient with hepatitis B virus/hepatitis C virus coinfection. Hepatol Res. 2016;46:489–91.CrossRefGoogle Scholar
Wang C, Ji D, Chen J, et al. Hepatitis due to reactivation of HBV in endemic areas among patients with hepatitis C treated with direct-acting antiviral agents. Clin Gastroenterol Hepatol. 2017;15:132–6.CrossRefGoogle Scholar
Chen G, Wang C, Chen J, et al. Hepatitis B reactivation in hepatitis B and C coinfected patients treated with antiviral agents: a systematic review and meta-analysis. Hepatology. 2017;66:13–26.CrossRefGoogle Scholar
Gish RG. HBV/HCV Coinfection and Possible Reactivation of HBV Following DAA Use. Gastroenterol Hepatol (N Y). 2017;13:292–5.Google Scholar
Wang XX, Luo BF, Jiang HJ, et al. Recovery of natural killer cells is mainly in post-treatment period in chronic hepatitis C patients treated with sofosbuvir plus ledipasvir. World J Gastroenterol. 2018;24:4554–64.CrossRefGoogle Scholar
Borrego F, Ulbrecht M, Weiss EH, Coligan JE, Brooks AG. Recognition of human histocompatibility leukocyte antigen (HLA)-E complexed with HLA class I signal sequence-derived peptides by CD94/NKG2 confers protection from natural killer cell-mediated lysis. J Exp Med. 1998;187:813–8.CrossRefGoogle Scholar
Yoshioka T, Tatsumi T, Miyagi T, et al. Frequency and role of NKp46 and NKG2A in hepatitis B virus infection. PLoS One. 2017;12:e0174103.CrossRefGoogle Scholar