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

Han-Ji Jiang¹, Xiao-Xiao Wang¹, Bi-Fen Luo¹

¹Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University Hepatology Institute, Peking University People's Hospital, No. 11 Xizhimen South Street, Beijing, 100044, People's Republic of China.

Clinical and Experimental Medicine

|June 21, 2019

Abstract:

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. CD56^bright 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. CD56^bright NK cells play an important role in this process.

Insights

Direct antiviral agents (DAAs) cure hepatitis C virus (HCV) by altering natural killer (NK) cell function. While NK cell receptor expression changes during DAA therapy, their cytotoxic activity and HCV replication inhibition significantly improve post-treatment, normalizing immune function.

Area of Science:

Immunology
Virology
Hepatology

Background:

Direct antiviral agents (DAAs) offer a cure for chronic hepatitis C (CHC), but their impact on the innate immune system, particularly natural killer (NK) cells, remains debated.
Understanding NK cell subset dynamics and functional changes during and after DAA treatment is crucial for a comprehensive view of CHC eradication.

Purpose of the Study:

To investigate the functional alterations of NK cell subsets during and after DAA treatment in CHC patients.
To analyze changes in the expression of NK cell receptors (NKp46 and NKG2A) and their cytotoxic activity against HCV.

Main Methods:

Flow cytometry was used to assess NKp46 and NKG2A expression in NK cell subsets from 13 CHC patients before, during, and after sofosbuvir/ledipasvir treatment.
NK cell cytotoxicity was evaluated using a redirected killing assay, and HCV replication inhibition was measured after co-culturing NK cells with HCV-infected cells.

Main Results:

All patients achieved sustained virologic response. NKp46 expression decreased during treatment and normalized post-treatment, while NKG2A expression decreased both during and after treatment.
The ratio of NKp46 to NKG2A was upregulated post-treatment, indicating enhanced NK cell potential. Specific lysis and HCV replication inhibition by NK cells significantly increased after DAA therapy.
CD56bright NK cells showed less pronounced changes in frequency ratio but played a key role in the overall functional normalization observed post-treatment.

Conclusions:

DAA treatment effectively cures CHC and modulates NK cell function, leading to normalized immune activity.
Despite transient changes in receptor expression, NK cells exhibit enhanced cytotoxic potential and improved ability to inhibit HCV replication after DAA therapy.
CD56bright NK cells are integral to the functional recovery of the immune system following DAA treatment for chronic hepatitis C.

Read full analysis

Keywords:

Direct antiviral agents Function Hepatitis C virus Innate immune system Natural killer cells

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