HBsAg Dampened STING Associated Activation of NK Cells in HBeAg-Negative CHB Patients.
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ABSTRACT:
SUBMITTER: Zheng B
PROVIDER: S-EPMC8304816 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Compared with terrestrial mammals, bats have a longer lifespan and greater capacity to co-exist with a variety of viruses. In addition to cytosolic DNA generated by these viral infections, the metabolic demands of flight cause DNA damage and the release of self-DNA into the cytoplasm. However, whether bats have an altered DNA sensing/defense system to balance high cytosolic DNA levels remains an open question. We demonstrate that bats have a dampened interferon response due to the replacement of the highly conserved serine residue (S358) in STING, an essential adaptor protein in multiple DNA sensing pathways. Reversing this mutation by introducing S358 restored STING functionality, resulting in interferon activation and virus inhibition. Combined with previous reports on bat-specific changes of other DNA sensors such as TLR9, IFI16, and AIM2, our findings shed light on bat adaptation to flight, their long lifespan, and their unique capacity to serve as a virus reservoir.
| S-EPMC7104992 | biostudies-literature
Project description:Background & aimsHBsAg proteins are useful to identify HBV inactive carriers (ICs), but data on chronic hepatitis D (CHD) are scarce. This study aimed to describe HBsAg composition in CHD, its changes during the evolution, and the potential association with clinical outcomes. In addition, we assess the composition of HBsAg across different HBV genotypes and validate previous results on HBsAg proteins in an independent HBV cohort.MethodsQuantitative HBsAg, medium HBsAg proteins (MHBs), and large HBsAg proteins (LHBs) were measured in two cohorts. The first cohort consisted of patients with CHD. A cross-sectional study of samples from two European institutions (N = 46) was conducted. Outcomes were assessed in a retrospective-prospective study of those patients with a follow-up of >1 year (n = 36), and the longitudinal evolution of HBsAg proteins in those with samples >5 years apart (n = 12) was analysed. The second cohort consisted of patients with HBeAg-negative HBV, and a cross-sectional study was performed (N = 141).ResultsForty-one (89%) patients with CHD had detectable HDV-RNA, and the presence of HDV-RNA was associated with higher LHBs proportion (p = 0.010). Baseline MHBs (p = 0.051) and MHBs proportion (p = 0.086) tended to be higher in those developing clinical outcomes (9/36, 25%) after a median follow-up of 5.9 years. Patients in which HDV-RNA became spontaneously undetectable during follow-up (5/31, 16.1%) tended to present lower MHBs proportion (p = 0.085). In the longitudinal study, changes in LHBs proportion were observed (p = 0.041), whereas MHBs proportion remained stable (p = 0.209). Regarding HBV, ICs showed lower LHBs proportion (p = 0.027). LHBs and MHBs differed significantly according to HBV genotype, regardless of the HBV phase.ConclusionsPatients with CHD with detectable HDV-RNA presented higher LHBs proportion than those with undetectable HDV-RNA. A trend toward having higher baseline MHBs proportion was observed in patients who developed clinical outcomes or remained with detectable HDV-RNA. This study validates the different HBsAg composition in HBV ICs and reveals the HBV-genotype influence in HBsAg composition.Impact and implicationsThe composition of HBsAg in chronic hepatitis D differs in patients with detectable and undetectable HDV viral load and may help predict the likelihood of achieving undetectable HDV viraemia and the development of clinical events such as decompensation. The composition of the surface antigen is also useful to distinguish inactive carriers of HBV, and it varies according to HBV genotype.
| S-EPMC10514556 | biostudies-literature
Project description:Many factors are associated with post-treatment relapse in CHB patients, and there are no effective factors to predict relapse. In this study, we investigate the influence factors associated with post-treatment relapse and their predictive value in HBeAg positive CHB (eP-CHB).The factors associated with post-treatment relapse were analyzed firstly by a retrospective study in eP-CHB. Variables included age, sex, regimen, baseline HBeAg and HBV DNA level, total course of treatment as well as duration of consolidation therapy after HBeAg seroconversion. The predictive effects of the influence factors were evaluated in an eP-CHB prospective cohort.89 patients were enrolled in the retrospective study, 42(47.2%) relapsed after discontinuation of treatment. Factors related to post-treatment relapse were total course of treatment, duration of consolidation therapy and baseline HBV DNA level. Relapse rates in patients with total course >36 months, consolidation duration >12 months and baseline HBV DNA level < 1.0E+5IU/ml were lower than those of total course <24 months (P = 0.002), consolidation duration?12 months (P = 0.011) and baseline HBV DNA level > 1.0E+7IU/ml (P = 0.01) respectively. Patients with HBV DNA?1.0E+7IU/ml plus HBeAg<200COI at baseline had the highest relapse rate and cumulative relapse rate than the other three arms (P = 0.048 and 0.008 respectively). Logistic regression analysis demonstrated that baseline HBV DNA level, duration of consolidation therapy and combination of baseline HBV DNA and HBeAg (IgDNA/IgHBeAg) were independent factors to predict post-treatment relapse. The model based on baseline IgDNA/IgHBeAg and consolidation duration worked well in predicting post-treatment relapse in the prospective study and the accuracy, specificity, sensitivity, PPV and NPV for prediction were 80.3%, 81.1%, 79.2%, 73.1% and 85.7% respectively.Virological factors including baseline HBV DNA, HBeAg and treatment course were major influence factors associated with post-treatment relapse in eP-CHB. Patients with higher HBV DNA and lower HBeAg levels at baseline, shorter total course as well as consolidation therapy were more likely to develop relapse after discontinuation of therapy. The antiviral therapy in eP-CHB patients should be individually managed at different levels. It is better to treat those with higher viral load and lower HBeAg levels at baseline for a longer course, especially longer consolidation duration so as to decrease the relapse rate.
| S-EPMC4629894 | biostudies-literature
Project description:Nucleic acid polymers block the assembly of hepatitis B virus (HBV) subviral particles, effectively preventing hepatitis B surface antigen (HBsAg) replenishment in the circulation. Nucleic acid polymer (NAP)-based combination therapy of HBV infection or HBV/hepatitis D virus (HDV) co-infection is accompanied by HBsAg clearance and seroconversion, HDV-RNA clearance in co-infection, and persistent functional cure of HBV (HBsAg < 0.05 IU/ml, HBV-DNA target not dected, normal alanine aminotransferase) and persistent clearance of HDV RNA. An analysis of HBsAg isoform changes during quantitative HBsAg declines (qHBsAg), and subsequent treatment-free follow-up in the REP 301/REP 301-LTF (HBV/HDV) and REP 401 (HBV) studies was conducted. HBsAg isoforms were analyzed from frozen serum samples using Abbott Research Use Only assays for HBsAg isoforms (large [L], medium [M], and total [T]). The relative change over time in small HBsAg relative to the other isoforms was inferred by the change in the ratio over time of T-HBsAg to M-HBsAg. HBsAg isoform declines followed qHBsAg declines in all participants. No HBsAg isoforms were detectable in any participants with functional cure. HBsAg declines > 2 log10 IU/ml from baseline were correlated with selective clearance of S-HBsAg in 39 of 42 participants. Selective S-HBsAg decline was absent in 9 of 10 participants with HBsAg decline < 2 log10 IU/ml from baseline. Mild qHBsAg rebound during follow-up <10 IU/ml consisted mostly of S-HBsAg and M-HBsAg and not accompanied by significant covalently closed circular DNA activity. Conclusion: The faster observed declines in S-HBsAg indicate the selective clearance of subviral particles from the circulation, consistent with previous mechanistic studies on NAPs. Trace HBsAg rebound in the absence of HBV DNA may reflect HBsAg derived from integrated HBV DNA and not rebound of viral infection.
| S-EPMC9315123 | biostudies-literature
Project description:Our recent study showed a high rate of HBsAg seroconversion in inactive HBsAg carriers (IHCs) treated with pegylated IFN (PEG-IFN). To understand the immune-mediated component of the HBsAg seroconversion better, this study investigated the role of NK cells. A total of 44 IHCs were given 48 wk of PEG-IFN. Fifteen cases achieved HBsAg seroconversion (R group), whereas 29 failed (NR group). The proportion and activity (CD107α and IFN-γ production) of NK cells were measured before and during treatment. We found that the proportion of NK cells in the R group was higher than in the NR group at baseline and during PEG-IFN treatment, even when patients were matched for age, sex and treatment period. IFN- γ secretion and CD107α expression from NK cells in cases who achieved HBsAg seroconversion were significantly higher than patients matched for age, sex, HBsAg and treatment period in the NR group at baseline and during PEG-IFN treatment. We also found that in HBsAg seroconversion cases, NK cells activity increased after PEG-IFN treatment, especially before HBsAg seroconversion. These effects were not found in non-responders. In conclusion, we demonstrated that the increase of NK cells accompanied by enhanced activity during PEG-IFN treatment favoured HBsAg seroconversion for IHC, and that NK cells may play a role in HBV seroconversion.
| S-EPMC7556194 | biostudies-literature
Project description:Background: Hepatitis B surface antigen (HBsAg) and viral load are important clinical indicators for antiviral therapy. Few studies have evaluated viral sequence biomarkers predicting the risk of hepatocellular carcinoma (HCC) in the stage, which show a low serological response (HBsAg < 100 IU/ml) and high viral levels (HBV DNA > 2,000 IU/ml). This study aims to determine the trend of the biological prevalence within the pre-S/S regions of special model of inactive CHB infection. Methods: We used Sanger sequencing, quantitative HBV serology (HBeAg and HBsAg), and liver function index to identify whether HBV genome sequences are associated with long-term risk of further HCC progression in special inactive CHB infection. Results: HBV sequencing analysis of 28 CHB patients with special infectious pattern showed higher genetic diversity among four opening reading frames (ORFs) (p < 0.001). However, dN/dS ratios of HBsAg and pre-C/C regions in the experimental group showed no significantly different from those in the HCC group (p = 0.06), while significantly lower in polymerase and HBxAg regions of the experimental group (p < 0.001). In addition, seven positively selected sites were identified in pre-S1, five in pre-S2, and four in S, in which five sites (128H/135Q/135R/139L/141P) were among "α" determinant. Conclusions: These mutations in the pre-S/S region might be associated with the HCC phenotype of low HBsAg expression, with the P region possibly impacting high viral loads. Increased viral diversity across the HBV genome is also associated with low levels of HBsAg. The cumulative evolutionary changes in the HBV pre-S/S regions shows that facilitate immune evasion should be monitored individually. Due to the similarity of evolutionary characteristics in HCC, low serological responses and high viremia may be associated with the risk of further disease progression.
| S-EPMC8107265 | biostudies-literature
Project description:BackgroundHBeAg-negative chronic hepatitis B patients require long-term nucleos(t)ide analogues(NAs) because loss of surface antigen (HBsAg) is unusual. Low quantitative HBsAg (qHBsAg) levels can identify patients with higher probability of seroclearance. The aim of our study was to evaluate qHBsAg in HBeAg-negative patients receiving NAs to predict a reduction of HBsAg levels and seroclearance.MethodsRetrospective analysis of qHBsAg in HBeAg-negative patients before and at years 1, 3, 5, 8 and over of NAs treatment.ResultsFrom 1999 to 2015, HBsAg was quantified in 358 serum samples from 95 HBeAg-negative patients. Low qHBsAg (<120 IU/mL) was identified at baseline or during follow-up in 14% of patients and HBsAg loss in 4%. No baseline variables predicted seroclearance and only treatment duration predicted low qHBsAg. The annual decline of qHBsAg was -0.102 log IU/mL and the median time to HBsAg loss was 6.04 years. The decline was greater in patients achieving low HBsAg levels (-0.257) than in those who did not (-0.057)(p<0.001). The diagnostic accuracy (ROC curve, 95%CI) of qHBsAg delta at year 3 was 0.89 (0.81-0.97), with cut-off >0.3 log IU/mL showing a positive and negative predictive value of 42% and 100% to identify patients achieving low levels of HBsAg.ConclusionsReduction of qHBsAg is slow in HBeAg-negative patients receiving NAs, although low levels or faster qHBsAg decline may occur in 14%. A qHBsAg reduction >0.3 log IU/mL at year 3 can identify patients with a higher probability of achieving low levels and HBsAg seroclearance.
| S-EPMC5708657 | biostudies-literature
Project description:Backgrounds & aimsLiver inflammation is the main risk factor for developing liver fibrosis, cirrhosis, and even hepatocellular carcinoma in chronic hepatitis B (CHB) patients. To replace biopsy, additional non-invasive biomarkers to diagnose and grade liver necroinflammation are urgently required in clinical practice.MethodNinety-four CHB patients, including 74 HBeAg-positive and 20 HBeAg-negative patients, were enrolled and started entecavir or adefovir therapy. Serum HBV RNA, HBV DNA, HBsAg, hepatitis B core-related antigen (HBcrAg), ALT and AST levels, as well as intrahepatic HBV DNA and cccDNA were measured at baseline and during treatment. Liver inflammation was assessed at baseline and month 60 by liver biopsy. Inflammation regression was defined as a ≥1-grade decrease according to the Scheuer scoring system.ResultsIn HBeAg-positive CHB patients, at baseline, serum HBsAg and HBcrAg levels negatively correlated with inflammation grade, while ALT and AST levels positively correlated with inflammation grade. AST plus HBsAg exhibited excellent diagnostic ability for significant inflammation with an AUROC of 0.896. After 60 months of antiviral treatment, almost all the patients' liver inflammation ameliorated to G1, and no patients had inflammation progression.ConclusionBesides ALT and AST, serum HBsAg and HBcrAg correlated with inflammation grade in HBeAg-positive CHB patients before NAs treatment. Moreover, the combination of HBsAg and AST exhibited excellent diagnostic ability for significant inflammation.
| S-EPMC10102387 | biostudies-literature
Project description:Hepatitis B surface antigen (HBsAg) clearance is considered as functional cure in patients with chronic hepatitis B (CHB). This study aimed to assess the durability of HBsAg clearance achieved by interferon-based therapies in patients with CHB who were originally positive for hepatitis B envelope antigen (HBeAg). In this prospective study, HBeAg-positive CHB patients with confirmed HBsAg loss under interferon-based therapies were enrolled within 12 weeks from end of treatment and followed up for 48 weeks. Virological markers, biochemical indicators, and liver imaging examinations were observed every 3-6 months. Sustained functional cure was analysed as primary outcome. Factor associated with sustained HBsAg loss or reversion was also investigated. The rate of HBsAg loss sustainability was 91.8% (212/231). Patients receiving consolidation treatment for 12-24 weeks or ≥ 24 weeks had higher rates of sustained HBsAg negativity than those receiving consolidation treatment for < 12 weeks (98.3% and 91.2% vs. 86.7%, P = 0.068), and the former groups had significantly higher anti-HBs levels than the later (P < 0.05). The cumulative incidence of HBsAg reversion and HBV DNA reversion was 8.2% and 3.9%, respectively. Consolidation treatment of ≥ 12 weeks [odd ratio (OR) 3.318, 95% confidence interval (CI) 1.077-10.224, P = 0.037) was a predictor of sustained functional cure, and HBeAg-positivity at cessation of treatment (OR 12.271, 95% CI 1.076-139.919, P = 0.043) was a predictor of HBsAg reversion. Interferon-alpha induced functional cure was durable and a consolidation treatment of ≥ 12-24 weeks was needed after HBsAg loss in HBeAg-positive CHB patients.
| S-EPMC9243604 | biostudies-literature
Project description:BACKGROUND: Serum quantitative hepatitis B surface antigen (HBsAg) levels may be an important predictor of hepatitis B e antigen (HBeAg) seroconversion (SC) in HBeAg-positive chronic hepatitis B (CHB) patients during antiviral treatment. The pattern of HBsAg variation in CHB patients either with or without SC following tenofovir disoproxil fumarate (TDF) treatment is not clearly understood. METHODS: Twenty patients with full experimental data were enrolled, and liver biochemistry, serum HBV DNA, and circulating CD4+CD25+ regulatory T cell (Treg) levels were determined at baseline and every 12 weeks after the initiation of TDF treatment (for a total of 96 weeks). In addition, the relationship between HBsAg or HBeAg and alanine aminotransferase (ALT), HBV DNA and Treg levels in SC and non-SC patients was analyzed. RESULTS: In all, 9 patients had undergone HBeAg seroconversion by week 72 of TDF treatment, and biochemical and virological indexes and Treg percentages declined to normal levels. Furthermore, the positive correlation between HBsAg and ALT, HBV DNA and Treg levels was significant for SC patients, but not for non-SC patients. However, for HBeAg, significant positive correlations were or not observed for both SC and non-SC patients. CONCLUSIONS: The quantitation of HBsAg is a more useful indicator than HBeAg for distinguishing SC and non-SC patients during TDF treatment. Moreover, HBsAg may be related to immune regulatory property of CHB patients during antiviral treatment.
| S-EPMC4230803 | biostudies-other