Dataset Information

Metabolic interventions improve HBV envelope-specific T-cell responses in patients with chronic hepatitis B.

ABSTRACT:

Background

Restoration of HBV-specific T cell immunity is a promising approach for the functional cure of chronic Hepatitis B (CHB), necessitating the development of valid assays to boost and monitor HBV-specific T cell responses in patients with CHB.

Methods

We analyzed hepatitis B virus (HBV) core- and envelope (env)-specific T cell responses using in vitro expanded peripheral blood mononuclear cells (PBMCs) from patients with CHB exhibiting different immunological phases, including immune tolerance (IT), immune activation (IA), inactive carrier (IC), and HBeAg-negative hepatitis (ENEG). Additionally, we evaluated the effects of metabolic interventions, including mitochondria-targeted antioxidants (MTA), polyphenolic compounds, and ACAT inhibitors (iACAT), on HBV-specific T-cell functionality.

Results

We found that HBV core- and env-specific T cell responses were finely coordinated and more profound in IC and ENEG than in the IT and IA stages. HBV env-specific T cells were more dysfunctional but prone to respond to metabolic interventions using MTA, iACAT, and polyphenolic compounds than HBV core-specific T-cells. The responsiveness of HBV env-specific T cells to metabolic interventions can be predicted by the eosinophil (EO) count and the coefficient of variation of red blood cell distribution width (RDW-CV).

Conclusion

These findings may provide valuable information for metabolically invigorating HBV-specific T-cells to treat CHB.

SUBMITTER: Fu YL

PROVIDER: S-EPMC10522531 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Publications

Metabolic interventions improve HBV envelope-specific T-cell responses in patients with chronic hepatitis B.

Fu Yu-Long YL Zhou Shuang-Nan SN Hu Wei W Li Jing J Zhou Ming-Ju MJ Li Xiao-Yu XY Wang You-Yuan YY Zhang Peng P Chen Si-Yuan SY Fan Xing X Song Jin-Wen JW Jiao Yan-Mei YM Xu Ruonan R Zhang Ji-Yuan JY Zhen Cheng C Zhou Chun-Bao CB Yuan Jin-Hong JH Shi Ming M Wang Fu-Sheng FS Zhang Chao C

Hepatology international 20230328 5

<h4>Background</h4>Restoration of HBV-specific T cell immunity is a promising approach for the functional cure of chronic Hepatitis B (CHB), necessitating the development of valid assays to boost and monitor HBV-specific T cell responses in patients with CHB.<h4>Methods</h4>We analyzed hepatitis B virus (HBV) core- and envelope (env)-specific T cell responses using in vitro expanded peripheral blood mononuclear cells (PBMCs) from patients with CHB exhibiting different immunological phases, inclu ...[more]

PMID: 36976426

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Project description:Background & aimsFunctional cure of chronic HBV infection (CHB) without life-long treatment requires the restoration of defective HBV-specific humoral and cellular immunity. Therapeutic vaccines based on the major structural and non-structural proteins have been tested in patients with CHB but have shown scarce immunogenicity. BRII-179, also known as VBI-2601, is a novel formulation comprised of all 3 HBV surface envelope proteins (Pre-S1, Pre-S2, and S). Safety, antiviral activity, and immunogenicity of BRII-179 admixed with co-adjuvant interferon (IFN)-α were assessed in patients with CHB.MethodThis randomized, open-label, controlled phase Ib/IIa study included 2 dose levels, 20 μg BRII-179 (Part 1, n = 25) and 40 μg BRII-179 (Part 2, n = 24). Patients, virally suppressed under nucleos(t)ide analogue (NA) therapy were randomized 1:2:2 into 3 cohorts in Part 1 and 1:1 into 2 cohorts in Part 2 to receive 4 monthly intramuscular injections of BRII-179 admixed with/without 3 MIU IFN-α. Antibody and cellular responses to HBsAg, as well as evolution of circulating HBsAg were monitored.ResultsBoth 20 μg and 40 μg BRII-179 with/without IFN-α were well tolerated with no severe adverse events. BRII-179 induced anti-HBs responses in >30% patients in all treatment cohorts, however, moderate anti-Pre-S1 or anti-Pre-S2 antibody responses were only observed in patients receiving BRII-179 with IFN-α. BRII-179 also restored S-, Pre-S1-, Pre-S2-specific IFN-γ-producing T-cells in the majority of treated patients. Overall, no notable reduction of HBsAg was observed after BRII-179 treatment.ConclusionIn patients with CHB under NA therapy, BRII-179 with/without IFN-α exhibited a good safety profile and induced HBV-specific B- and T-cell immune responses. These data support further clinical evaluation of BRII-179 in combination with other therapies.Clinical trial numberACTRN12619001210167.Lay summaryBRII-179 is a therapeutic vaccine designed to improve the immune response in patients with chronic hepatitis B. In this study, BRII-179 alone or with a low dose of interferon-α was safe, well tolerated, and induced enhanced HBV-specific antibody and T-cell responses in patients with chronic hepatitis B. However, BRII-179 treatment alone had minimal effect on patient's virological status. The potential of BRII-179 to achieve a functional cure in conjunction with other agents is being evaluated in the clinic.

Project description:BackgroundThe clinical routine test of HBV-specific T cell reactivity is still limited due to the high polymorphisms of human leukocyte antigens (HLA) in patient cohort and the lack of universal detection kit, thus the clinical implication remains disputed.MethodsA broad-spectrum peptide library, which consists of 103 functionally validated CD8+ T-cell epitopes spanning overall HBsAg, HBeAg, HBx and HBpol proteins and fits to the HLA polymorphisms of Chinese and Northeast Asian populations, was grouped into eight peptide pools and was used to establish an ELISpot assay for enumerating the reactive HBV-specific T cells in PBMCs. Totally 294 HBV-infected patients including 203 ones with chronic hepatitis B (CHB), 13 ones in acute resolved stage (R), 52 ones with liver cirrhosis (LC) and 26 ones with hepatocellular carcinoma (HCC) were detected, and 33 CHB patients were longitudinally monitored for 3 times with an interval of 3-5 months.ResultsThe numbers of reactive HBV-specific T cells were significantly correlated with ALT level, HBsAg level, and disease stage (R, CHB, LC and HCC), and R patients displayed the strongest HBV-specific T cell reactivity while CHB patients showed the weakest one. For 203 CHB patients, the numbers of reactive HBV-specific T cells presented a significantly declined trend when the serum viral DNA load, HBsAg, HBeAg or ALT level gradually increased, but only a very low negative correlation coefficient was defined (r = - 0.21, - 0.21, - 0.27, - 0.079, respectively). Different Nucleotide Analogs (NUCs) did not bring difference on HBV-specific T cell reactivity in the same duration of treatment. NUCs/pegIFN-α combination led to much more reactive HBV-specific T cells than NUCs monotherapy. The dynamic numbers of reactive HBV-specific T cells were obviously increasing in most CHB patients undergoing routine treatment, and the longitudinal trend possess a high predictive power for the hepatitis progression 6 or 12 months later.ConclusionThe presented method could be developed into an efficient reference method for the clinical evaluation of cellular immunity. The CHB patients presenting low reactivity of HBV-specific T cells have a worse prognosis for hepatitis progression and should be treated using pegIFN-α to improve host T-cell immunity.

Project description:Background and aims: In chronic HBV infection elevated ROS levels by dysfunctional mitochondria can cause increased protein oxidation, proteostasis engulfment and DNA damage in exhausted virus-specific CD8 T cells. Aim of this study was to understand how these defects are mechanistically interconnected, to further elucidate T cell exhaustion pathogenesis and to design novel T cell-based therapies. Methods: DNA damage and DNA repair mechanisms, including parylation, CD38 expression, histone acetylation and telomere length were studied by flow cytometry in dextramer-stained HBV-specific CD8 T cells from chronic HBV patients. FLU-specific CD8 cells from the same patients and healthy subjects served as controls. Correction of intracellular signaling alterations and improvement of anti-viral T cell functions by the NAD precursor NMN and by CD38 inhibition, was assessed by fluorescent probes and antibodies in flow cytometry Results: Elevated DNA damage was associated with defective DNA repair processes, including NAD-dependent parylation, in HBV-specific CD8 cells of chronic HBV patients. NAD depletion in these patients was indicated by the overexpression of CD38, the major NAD consumer, and by the significant improvement of DNA repair mechanisms, mitochondrial and proteostasis functions and epigenetic regulation by NAD supplementation, which could also improve the overall HBV-specific antiviral CD8 T cell function. Conclusions: Our study delineates a model of CD8 T cell exhaustion whereby multiple functionally interconnected intracellular defects, including telomere shortening, are causally related to NAD depletion suggesting similarities between T cell exhaustion and cell senescence. Correction of these deregulated intracellular functions by NAD supplementation can also restore anti-viral CD8 T cell activity and thus represents a promising potential therapeutic strategy for chronic HBV infection. Gene expression profiling analysis using data derived from low input RNA-seq of patients' virus-specific CD8 T cells either upon in vitro culture or ex-vivo isolated from total PBMCs

Dataset Information

Metabolic interventions improve HBV envelope-specific T-cell responses in patients with chronic hepatitis B.

Background

Methods

Results

Conclusion

Publications

Metabolic interventions improve HBV envelope-specific T-cell responses in patients with chronic hepatitis B.

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