Variants in STAT4 Associated With Cure of Chronic HBV Infection in HBeAg-positive Patients Treated With Pegylated Interferon-alpha

Chen, Haitao; Sun, Jian; Zhou, Bin; Xie, Qing; Liang, Xier; Fan, Rong; Conran, Carly; Xu, Jianfeng; Ji, Yuan; Zhang, Xinxin; Sun, Lihua; Jia, Jidong; Wang, Guiqiang; Hou, Jinlin; Jiang, Deke

doi:10.1016/j.cgh.2019.04.044

Cited by 19 publications

(44 citation statements)

References 31 publications

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“…Based on the curative effects in patients at the 24-week posttreatment (week 72) follow-up, HBeAg-positive CHB patients were divided into the SR (n = 18) and nonresponse (NR; n = 19) groups. An SR was defined according to previous studies 25,26 as HBeAg < 1 S/CO, HBV DNA < 500 IU/ml, and ALT < 40 U/L. Patients were categorized as having a NR if they did not meet all of the above criteria.…”

Section: Methodsmentioning

confidence: 99%

Taurocholic acid inhibits the response to interferon-α therapy in patients with HBeAg-positive chronic hepatitis B by impairing CD8+ T and NK cell function

Xun

Lin

et al. 2021

Cell Mol Immunol

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Pegylated interferon-alpha (PegIFNα) therapy has limited effectiveness in hepatitis B e-antigen (HBeAg)-positive chronic hepatitis B (CHB) patients. However, the mechanism underlying this failure is poorly understood. We aimed to investigate the influence of bile acids (BAs), especially taurocholic acid (TCA), on the response to PegIFNα therapy in CHB patients. Here, we used mass spectrometry to determine serum BA profiles in 110 patients with chronic HBV infection and 20 healthy controls (HCs). We found that serum BAs, especially TCA, were significantly elevated in HBeAg-positive CHB patients compared with those in HCs and patients in other phases of chronic HBV infection. Moreover, serum BAs, particularly TCA, inhibited the response to PegIFNα therapy in HBeAg-positive CHB patients. Mechanistically, the expression levels of IFN-γ, TNF-α, granzyme B, and perforin were measured using flow cytometry to assess the effector functions of immune cells in patients with low or high BA levels. We found that BAs reduced the number and proportion and impaired the effector functions of CD3+CD8+ T cells and natural killer (NK) cells in HBeAg-positive CHB patients. TCA in particular reduced the frequency and impaired the effector functions of CD3+CD8+ T and NK cells in vitro and in vivo and inhibited the immunoregulatory activity of IFN-α in vitro. Thus, our results show that BAs, especially TCA, inhibit the response to PegIFNα therapy by impairing the effector functions of CD3+CD8+ T and NK cells in HBeAg-positive CHB patients. Our findings suggest that targeting TCA could be a promising approach for restoring IFN-α responsiveness during CHB treatment.

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Section: Methodsmentioning

confidence: 99%

Taurocholic acid inhibits the response to interferon-α therapy in patients with HBeAg-positive chronic hepatitis B by impairing CD8+ T and NK cell function

Xun

Lin

et al. 2021

Cell Mol Immunol

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“…Additionally, 648 HBeAg-positive CHB patients who treated with Peg-IFNα at the dose of 180 µg/week for 48 weeks and a treatment-free follow-up for 24 weeks (Peg-IFNα-2a, n=324; Peg-IFNα-2b, n=324) were used to evaluate the association of single-nucleotide polymorphism (SNP) rs1799821 genotype with complete response (CR, defined as HBeAg seroconversion and an HBV DNA level < 2000 IU/mL at week 72). Details of patients were previously reported ( 19 , 20 ). Patients suffering from autoimmune diseases, other active diseases, or coinfection with HAV, HCV, HDV, or HIV were excluded.…”

Section: Methodsmentioning

confidence: 99%

“…Results of LDR corresponded with the results of sequencing for the randomly selected DNA samples from each genotype. Genotyping of rs1799821 in patients treated with Peg-IFNα was performed as previously described ( 20 ).…”

Section: Methodsmentioning

confidence: 99%

High L-Carnitine Levels Impede Viral Control in Chronic Hepatitis B Virus Infection

et al. 2021

Front. Immunol.

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Persistent antigen exposure during chronic hepatitis B infection leads to exhausted immune responses, thus impeding viral control. In recent years, immunometabolism opens new therapeutic possibilities for the modulation of immune responses. Herein, we investigated the immunomodulatory effect of L-carnitine (L-Cn) on immune cells in chronic HBV infection. In this study, 141 treatment-naïve patients with chronic HBV infection, 38 patients who achieved HBsAg loss following antiviral treatment, and 47 patients who suffered from HBV-related HCC from real-life clinical practice were recruited. The plasma L-Cn levels were measured by ELISA. RNA sequencing was conducted to define the transcriptional profiles of peripheral blood mononuclear cells after L-Cn stimulation. In vitro assays were performed to assess the effect of L-Cn on immune cells; the frequencies and function of immune cells were analyzed by flow cytometry. We found that compared with patients with HBsAg loss, patients with HBsAg positivity and patients who suffered from HBV-related HCC had higher levels of L-Cn, and the plasma levels of L-Cn in the HBeAg-positive chronic hepatitis patients who had elevated ALT were significantly higher than that of HBeAg-negative chronic infection and HBsAg loss groups. Moreover, a positive correlation between plasma levels of L-Cn and HBsAg levels was found. Additionally, RNA sequencing analysis demonstrated that L-Cn altered the transcriptional profiles related to immune response. In vitro assays revealed that L-Cn suppressed the proliferation of and IFN-γ production by CD4+ and CD8+ T cells. It also down-regulated the proliferation and IgG production of B cells. Notably, L-Cn enhanced IL-10 secretion from regulatory T cells and up-regulated the expression of inhibitory receptors on T cells. Moreover, a variant in CPT2 (rs1799821) was confirmed to be associated with L-Cn levels as well as complete response in CHB patients following Peg-IFNα antiviral therapy. Taken together, the immunosuppressive properties of L-Cn may hinder the control of HBV in chronic HBV infection, implicating that L-Cn manipulation might influence the prognosis of patients with HBV infection.

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“…In addition, STAT4 rs7574865 was reported to be associated with CHB susceptibility as well as HBV natural clearance [90][91][92]. Recently, Jiang DK et al reported that STAT4 rs7574865 is a reliable predictor of response to IFNα therapy, a first-line therapy for CHB, in hepatitis B e antigen (HBeAg)-positive CHB patients [93,94]. Hepatectomy is a main therapy for HCC, and lower STAT4 expression showed higher incidence of recurrence after this procedure.…”

Section: Chb and Hccmentioning

confidence: 99%

STAT4: an immunoregulator contributing to diverse human diseases

Yang¹,

Mai²,

Peng³

et al. 2020

Int. J. Biol. Sci.

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Signal transducer and activator of transcription 4 (STAT4) is a member of the STAT family and localizes to the cytoplasm. STAT4 is phosphorylated after a variety of cytokines bind to the membrane, and then dimerized STAT4 translocates to the nucleus to regulate gene expression. We reviewed the essential role played by STAT4 in a wide variety of cells and the pathogenesis of diverse human diseases, especially many kinds of autoimmune and inflammatory diseases, via activation by different cytokines through the Janus kinase (JAK)-STAT signaling pathway.

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Variants in STAT4 Associated With Cure of Chronic HBV Infection in HBeAg-positive Patients Treated With Pegylated Interferon-alpha

Cited by 19 publications

References 31 publications

Taurocholic acid inhibits the response to interferon-α therapy in patients with HBeAg-positive chronic hepatitis B by impairing CD8+ T and NK cell function

Taurocholic acid inhibits the response to interferon-α therapy in patients with HBeAg-positive chronic hepatitis B by impairing CD8+ T and NK cell function

High L-Carnitine Levels Impede Viral Control in Chronic Hepatitis B Virus Infection

STAT4: an immunoregulator contributing to diverse human diseases

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