Serum HBV pregenomic RNA exhibited opposite associations with NKdim and NKbright cell immunity in treatment-naïve chronic hepatitis B patients

Hepatitis B virus (HBV) pregenomic RNA (pgRNA) is a new biomarker that reflects HBV replication, but its relationship with natural killer (NK) cell immunity in chronic hepatitis B (CHB) is unknown. We assessed serum HBV pgRNA levels in 323 CHB patients by reverse transcription-polymerase chain reaction, assessed cytokine production and activation and inhibitory markers of NK cells by flow cytometry, and measured serum cytokines by enzyme-linked immunosorbent assays. Among the different CHB phases, the serum HBV pgRNA level was highest in the immune tolerant (IT) and immune active (IA) phases. Regarding NK and NKdim cells, HBV pgRNA was negatively associated with frequencies, but positively associated with NKp44 and NKp46 expression (activation markers). Regarding NKbright cells, serum HBV pgRNA was positively associated with frequency and PD1 expression (inhibitory marker), but negatively associated with NKp44 and NKp46. Serum HBV pgRNA was not associated with NKp30 (activation marker) on NK cells or subsets. Lastly, serum HBV pgRNA was positively correlated with the levels of serum IL-7 and IL-12P40 (NK cell-promoting cytokines) and negatively correlated with serum prostaglandin E2 level (which negatively regulates NK cells). In conclusion, we found varied relationships between serum HBV pgRNA and NK cells and subsets, indicating that HBV pgRNA may play a complicated role in NK cell-related immunity, providing new information on HBV and host immunity.

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Treatment with Telbivudine Positively Regulates Antiviral Immune Profiles in Chinese Patients with Chronic Hepatitis B

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02181-12 ◽

2012 ◽

Vol 57 (3) ◽

pp. 1304-1311 ◽

Cited By ~ 11

Author(s):

Liang Ma ◽

Yan-Jun Cai ◽

Lei Yu ◽

Jun-Yan Feng ◽

Juan Wang ◽

...

Keyword(s):

T Cells ◽

Chronic Hepatitis ◽

Hepatitis B ◽

Nk Cells ◽

Chronic Hepatitis B ◽

Nk Cell ◽

Hbv Dna ◽

Chinese Patients ◽

Cell Immunity ◽

The Impact

ABSTRACTChronic infection with hepatitis B virus (HBV) is associated with impairment of T and NK cell immunity. This study was aimed at investigating the impact of treatment with telbivudine (LDT) on T and NK cell immunity in patients with chronic hepatitis B (CHB). A total of 54 CHB patients and 30 healthy controls (HC) were recruited. Individual patients were treated orally with 600 mg LDT daily for 13 months. The serum HBV DNA loads, the levels of the HBV-related biomarkers alanine aminotransferase (ALT) and aspartate transaminase (AST), and the numbers of different subsets of peripheral T and NK cells in subjects were measured before and longitudinally after LDT treatment. Following treatment with LDT, the serum HBV DNA loads and the percentages of HBsAg- or HBeAg-seropositive cases were gradually reduced, accompanied by decreased levels of serum ALT and AST. In comparison with the HC, fewer CD3−CD56+and CD244+NK cells and CD3+CD8+T cells, lower frequencies of cytokine+CD4+T cells, and more CD3+CD4+, CD4+CD25+Foxp3+, CD4+CD25+CD127low, and CD8+PD-1+T cells were detected in CHB patients. Treatment with LDT increased the numbers of NK and CD8+cells and the frequencies of cytokine+CD4+T cells but reduced the numbers of CD4+CD25+Foxp3+, CD4+CD25+CD127low, and CD8+PD-1+T cells in CHB patients. The frequencies of cytokine+CD4+T cells were negatively associated with the levels of serum HBV DNA, ALT, and AST. Thus, treatment with LDT inhibits HBV replication, modulates T and NK cell immunity, and improves liver function in Chinese patients with CHB.

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The Characteristics of Natural Killer Cells in Chronic Hepatitis B Patients Who Received PEGylated-Interferon versus Entecavir Therapy

BioMed Research International ◽

10.1155/2021/2178143 ◽

2021 ◽

Vol 2021 ◽

pp. 1-14

Author(s):

Weihua Cao ◽

Minghui Li ◽

Lu Zhang ◽

Yao Lu ◽

Shuling Wu ◽

...

Keyword(s):

Chronic Hepatitis ◽

Hepatitis B ◽

Nk Cells ◽

Natural Killer ◽

Chronic Hepatitis B ◽

Nk Cell ◽

Antiviral Treatment ◽

Pegylated Interferon ◽

Cell Frequency ◽

Subgroup Analyses

Background. To explore the role of natural killer (NK) cells in the process of hepatitis B virus (HBV) clearance and whether their phenotype is related to antiviral treatment outcome in chronic hepatitis B (CHB) patients. Method. We performed a single-center prospective cohort study to analyze changes of NK cells at weeks 12 and 24 from baseline in CHB patients who received PEGylated-interferon- (PEG-IFN-) α-2a versus entecavir. The frequencies of NK, CD56bright, CD56dim, IFNAR2+, NKp46+, NKp46bright, and NKp46dim NK cells and mean fluorescence intensity (MFI) of receptors NKp46 and IFNAR2 on the surface of NK cells were measured. Subgroup analyses were performed by comparing treatment responders versus nonresponders with aforementioned parameters in each group. Results. In PEG-IFN-α-treated patients, posttreatment CD56bright NK cell frequency increased, but CD56dim NK cell frequency decreased. Additionally, receptor NKp46 and IFNAR2 expression enhanced. In entecavir-treated patients, although NK cell frequency increased, CD56bright and CD56dim NK cell frequencies and IFNAR2 expression did not differ between baseline and posttreatment. In subgroup analyses, posttreatment CD56bright NK cell frequency and IFNAR2 expression significantly increased in PEG-IFN-α responders from baseline, while changes were absent in PEG-IFN-α nonresponders and entecavir treatment responders. Among patients with HBV viremia after entecavir therapy, NK cell frequency significantly increased, whereas NKp46bright and IFNAR2+ NK frequency and IFNAR2 MFI significantly decreased at 12 and 24 weeks from baseline. Conclusions. In CHB patients, PEG-IFN-α treatment significantly enhanced NK cell frequency and function when compared to entacavir. Positive treatment responses to either interferon or entecavir were associated with NK cell function improvement. This trial is registered with clinical trial registration no. NCT03208998.

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The Good and the Bad of Natural Killer Cells in Virus Control: Perspective for Anti-HBV Therapy

International Journal of Molecular Sciences ◽

10.3390/ijms20205080 ◽

2019 ◽

Vol 20 (20) ◽

pp. 5080 ◽

Cited By ~ 3

Author(s):

Paola Fisicaro ◽

Marzia Rossi ◽

Andrea Vecchi ◽

Greta Acerbi ◽

Valeria Barili ◽

...

Keyword(s):

T Cells ◽

Chronic Hepatitis ◽

T Cell ◽

Hepatitis B ◽

Nk Cells ◽

Natural Killer ◽

Chronic Hepatitis B ◽

Nk Cell ◽

Viral Control ◽

Cell Functions

Immune modulatory therapies are widely believed to represent potential therapeutic strategies for chronic hepatitis B infection (CHB). Among the cellular targets for immune interventions, Natural Killer (NK) cells represent possible candidates because they have a key role in anti-viral control by producing cytokines and by exerting cytotoxic functions against virus-infected cells. However, in patients with chronic hepatitis B, NK cells have been described to be more pathogenic than protective with preserved cytolytic activity but with a poor capacity to produce anti-viral cytokines. In addition, NK cells can exert a regulatory activity and possibly suppress adaptive immune responses in the setting of persistent viral infections. Consequently, a potential drawback of NK-cell targeted modulatory interventions is that they can potentiate the suppressive NK cell effect on virus-specific T cells, which further causes impairment of exhausted anti-viral T cell functions. Thus, clinically useful NK-cell modulatory strategies should be not only suited to improve positive anti-viral NK cell functions but also to abrogate T cell suppression by NK cell-mediated T cell killing. This review outlines the main NK cell features with a particular focus on CHB infection. It describes different mechanisms involved in NK-T cell interplay as well as how NK cells can have positive anti-viral effector functions and negative suppressive effects on T cells activity. This review discusses how modulation of their balance can have potential therapeutic implications.

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