Clinical and Experimental Medicine

, Volume 19, Issue 3, pp 299–308 | Cite as

Direct antiviral agents upregulate natural killer cell potential activity in chronic hepatitis C patients

  • Han-ji Jiang
  • Xiao-xiao Wang
  • Bi-fen Luo
  • Xu Cong
  • Qian Jin
  • Hong Qin
  • Hai-ying Zhang
  • Xiang-sha Kong
  • Lai Wei
  • Bo FengEmail author
Original Article


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 



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.


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University Hepatology InstitutePeking University People’s HospitalBeijingPeople’s Republic of China

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