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ABSTRACT: To investigate the correlation between the HBeAg and the properties of HBV-specific CD8 T cells, as well as liver injury, serum HBV markers, liver histology, the frequency and phenotypic characteristics of CD4(+)CD25(+) Treg and HBV-pentamer(+) CD8 T cells were measured. No significant differences between the median serum ALT levels, the frequency and Foxp3 expression of CD4(+)CD25(+) Treg, and liver fibrosis were observed. Higher HBV DNA levels in HBeAg(+) patients were observed, while liver necroinflammation was more severe in HBeAg(-) patients. Differences in HBV-pentamer(+) T cell frequency were not significant, but increased PD-1 and CTLA-4 expression on HBV-specific CD8 T cells was seen in the HBeAg(+) group. HBV-peptide stimulation with anti-PD-L1 and anti-CTLA-4 significantly increased the proliferation in PBMCs from both groups, but enhanced IFN-γ production only in the HBeAg(+) patients. Therefore, HBeAg persistency in CHB patients probably increased the expression of PD-1 and CTLA-4 on HBV-specific CD8 T cells, which may be associated with the low intensity of T cell responses and high HBV DNA load.
Journal of Clinical Immunology 12/2010; 31(2):195-204. · 3.08 Impact Factor
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Dongjiu Zhao,
Xianfeng Wang,
Guohua Lou,
Guoping Peng, Jie Li,
Haihong Zhu,
Feng Chen,
Shuping Li,
Dongcheng Liu,
Zhi Chen,
Zhenggang Yang
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ABSTRACT: APOBEC3G (A3G) is an intrinsic antiretroviral factor which can inhibit Hepatitis B virus (HBV) replication. This antiviral activity mainly depends on A3G incorporation into viral particles. However, the mechanisms of A3G packaging into HBV particles have not been well characterized. In this paper, we demonstrated that A3G interacted with the HBV core protein (HBc) directly in co-transfected HepG2 cells using the fluorescence resonance energy transfer (FRET) approach. In addition, we further found that this interaction did not require other factors in vitro using surface plasmon resonance (SPR) technology on BIAcore 3000. While cellular RNA or viral RNA was added to A3G protein solution before flow through the BIAcore chip, the interaction was not affected. In conclusion, these results suggest the possibility that A3G is incorporated into HBV viral particles via direct binding with HBc protein.
Virus Research 08/2010; 151(2):213-9. · 2.94 Impact Factor
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ABSTRACT: T-helper (Th) 17 cells have been shown to have an important role in host defense against viral infection. However, little is known about the regulation of Th17 cells in hepatitis B virus (HBV) infections. Peripheral blood mononuclear cells (PBMCs) isolated from patients with chronic hepatitis B (CHB) were stimulated with anti-interleukin (IL)-10 antibody or recombinant IL-10. The frequency of hepatitis B core antigen (HBcAg)-specific Th17 cells was characterized and produced cytokines were determined by flow cytometry. A low frequency of Th17 cells and a high frequency of Th1 cells were detected in CHB patients. HBcAg stimulation promoted IL-17A, IL-22, IL-23, IL-6, transforming growth factor (TGF)-β and IL-10 production by PBMCs from CHB patients, but not from healthy controls. Furthermore, endogenous IL-10 inhibited HBcAg-stimulated production of IL-17A, IL-22, IL-6 and IL-23, but not TGF-β. Treatment with IL-10 inhibited the HBcAg-stimulated activation of Th17 cells, whereas anti-IL-10 antibody significantly increased the frequency of Th17 and Th1 cells, but not that of CD4(+)CD25(+) regulatory T cells, associated with upregulating RORγt expression in CD4(+) T cells. HBcAg stimulated the production of IL-10, which negatively regulated HBcAg-specific Th17 cell responses in CHB patients. Our findings may represent one evasion strategy for HBV to subvert specific antiviral responses in humans.
Immunology and Cell Biology 05/2010; 88(8):834-41. · 3.66 Impact Factor
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ABSTRACT: Th17 cells have been shown to mediate host defensive mechanisms in various infections, but their role in HBV infection in humans has not been well characterized. In this study, we analyzed the frequency and cytokines secretion of circulating Th17 cells in HBV infected patients with different statuses, and also evaluated the potential association of Th17 frequency with the levels of liver injury.
The study population consisted of 133 subjects, including 40 mild chronic hepatitis B (CHB) patients, 37 severe CHB patients, 20 acute hepatitis B (AHB) patients and 36 healthy controls. The frequency of circulating Th17 cells were carried out by intracellular cytokine staining analysis and serum IL-10 levels were measured by ELISA.
Our data shown that AHB and severe CHB patients had a significant increase of Th17 cells frequency in peripheral blood compared with mild CHB patients and healthy control (both P < 0.05). The elevated prevalence of Th17 cells is positively associated with the increased serum ALT levels in severe CHB patients (r= 0.457, P= 0.004) but had no correlation with serum HBV DNA load. In addition, the serum IL-10 were negatively correlated with the frequency of Th17 cells in PBMC from patients with chronic HBV infection (r=-0.452, P < 0.01).
Th17 cells may contribute to the disease progression and pathogenesis of liver injury in HBV infected patients, and the induction of IL-10 may be one mechanism of constraining pro-inflammatory Th17 responses.
Journal of Gastroenterology and Hepatology 04/2010; 25(4):750-7. · 2.87 Impact Factor
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ABSTRACT: As a major therapy for hepatitis B virus (HBV) infection, Interferon alpha (IFN-alpha) triggers intracellular signal transduction including JAK-STAT pathway to produce various antiviral effector mechanisms. However, patients with chronic hepatitis B usually show low response to IFN-alpha treatment and the underlying mechanism remains unclear. In the present study, HepG2 and HepG2.2.15 cells were used to examine the Type I IFN receptors expression, phosphorylation and methylation of STAT1. STAT1-PIAS1 interaction in cells was tested by protein co-immunoprecipitation. The potential improvement of S-adenosylmethionine (SAM) in the antiviral effect of IFN-alpha was also investigated. Our data demonstrated that both chains of the Type I IFN receptors were expressed for a much higher extent in HepG2.2.15 cells than in HepG2 cells. HBV inhibited dramatically the methylation rather than the phosphorylation of STAT1, which was consistent with an increased STAT1-PIAS1 interaction. Combined with IFN-alpha, SAM treatment effectively improved STAT1 methylation and attenuated STAT1-PIAS1 binding, followed by increased PKR and 2',5'-OAS mRNA expression, thus significantly reducing the HBsAg, HBeAg protein levels and HBV DNA load in the supernatant of HepG2.2.15 cells. Less STAT1 methylation and subsequent increased STAT1-PIAS1 interaction are involved in the mechanism of the IFN-alpha-antagonistic activity of HBV. By improving STAT1 methylation, SAM can enhance the antiviral effect of IFN-alpha.
Antiviral research 10/2009; 85(3):463-9. · 3.61 Impact Factor
