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Interferon-alpha (IFN-α) is a first-line drug for treating chronic hepatitis B (CHB). Guanylate-binding protein 1 (GBP1) is one of the interferon-stimulating factors, which participates in the innate immunity of the host and plays an antiviral and antibacterial role. In this study, we explored how GBP1 is involved in IFN-α antiviral activity against HBV. Before being gathered, HepG2-NTCP and HepG2 2.15 cells were transfected with the wild-type hGBP1 plasmid or si-GBP1, respectively, and followed by stimulation with Peg-IFNα-2b. We systematically explored the role of GBP1 in regulating HBV infection in cell models. Additionally, we also examined GBP1 levels in CHB patients. GBP1 activity increased, and its half-life was prolonged after HBV infection. Overexpression of GBP1 inhibited the production of HBsAg and HBeAg, as well as HBs protein and HBV total RNA levels, whereas silencing of GBP1 inhibited its ability to block viral infections. Interestingly, overexpressing GBP1 co-treatment with Peg-IFNα-2b further increased the antiviral effect of IFN-α, while GBP1 silencing co-treatment with Peg-IFNα-2b partly restored its inhibitory effect on HBV. Mechanistically, GBP1 mediates the anti-HBV response of Peg-IFNα-2b by targeting HBs. Analysis of clinical samples revealed that GBP1 was elevated in CHB patients and increased with Peg-IFNα-2b treatment, while GBP1 showed good stability in the interferon response group. Our study demonstrates that GBP1 inhibits HBV replication and promotes HBsAg clearance. It is possible to achieve antiviral effects through the regulation of IFN-α induced immune responses in response to HBV., (© 2024 Yadi Li et al., published by Sciendo.)

Introduction: The seeds of Brucea javanica (L.) Merr. (BJ) have been traditionally used to treat various types of cancers for many years in China. In this study, we systematically investigated a BJ oil emulsion (BJOE) produced from BJ seeds with the purpose of evaluating its antiviral effect against hepatitis B virus (HBV)., Methods: HepG2.215 (a wild-type HBV cell line), HepG2, and Huh7, transfected with wildtype (WT) or lamivudine-resistance mutant (LMV-MT) HBV replicon plasmids, were treated with different doses of BJOE and then used for pharmacodynamic evaluation. Cell viability was determined using CCK8 assay. The levels of HBsAg/HBeAg in cell cultured supernatant, HBcAg in cell lysis solution, and HBV DNA in both were evaluated., Results: BJOE at ≤5 mg/ml was nontoxic to carcinoma cell lines, but could significantly inhibit WT/LMV-MT HBV replication and HBs/e/c antigen expression in a dose-dependent manner by upregulating interleukin-6 (IL-6), demonstrating that it possesses moderate anti-HBV activity. As one of the major components of BJOE, bruceine B was found to play a dominant role in IL-6 induction and HBV inhibition., Discussion: Our results demonstrated that BJOE suppressed HBV replication by stimulating IL-6, indicating that it has promising clinical therapeutic potential for both WT and LMV-MT HBV., Competing Interests: Authors JL, WY were employed by GeneMind Biosciences Company Limited, Shenzhen, China. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Qin, Shen, Lai, Yang, Feng and Ding.)

As a member of the liver tropic virus family, hepatitis B virus (HBV) was thought to only infect and replicate within the liver. Sodium taurocholate co‑transporting polypeptide (NTCP) has been identified as a functional cellular receptor and a major determinant of liver tropism and HBV entry level species specificity. In the present study, the Oncomine database was used to explore differences in NTCP expression among cancerous and normal tissues. The results revealed that NTCP was highly expressed in breast cancer (BC), which was subsequently verified in clinical samples. Furthermore, in the BC tissue of patients with chronic HBV, HBV antigens, viral DNA/RNA and specific viral particles were detected via immunohistochemistry, ELISA, western blotting, reverse transcription‑quantitative PCR and electron microscopy. Different HBV biomarkers and Dane particles were detected in BC. Furthermore, high levels of HBV‑specific RNAs, the characteristic signals of HBV replication, were also detected, indicating that HBV infects BC tissue by binding to NTCP and replicating within. Based on the data of the present study, BC tissue may represent a second location of HBV infection and replication in addition to the liver.

Primary human hepatocytes (PHHs) are the 'gold standard' for investigating hepatitis B virus (HBV) infection and antiviral drugs. However, poor availability, variation between batches and ethical issues regarding PHHs limit their applications. The discovery of human sodium taurocholate co‑transporting polypeptide (hNTCP) as a functional HBV receptor has enabled the development of a surrogate model to supplement the use of PHHs. In the present study, the evolutionary distance of seven species was assessed based on single‑copy homologous genes. Based on the evolutionary distance and availability, PHHs and primary rabbit hepatocytes (PRHs) were isolated and infected with hNTCP‑recombinant lentivirus, and susceptibility to HBV infection in the two cell types was tested and compared. In addition, HBV infection efficiency of hNTCP‑expressing PPHs with pooled HBV‑positive serum and purified particles was determined. The potential use of HBV‑infected hNTCP‑expressing PPHs for drug screening was assessed. The results demonstrated that pigs and rabbits are closer to humans in the divergence tree compared with mice and rats, indicating that pigs and rabbits were more likely to facilitate the HBV post‑entry lifecycle. Following hNTCP complementation and HBV infection, PPHs and Huh7D human hepatocellular carcinoma cells, but not PRHs, exhibited increased hepatitis B surface antigen and hepatitis B e‑antigen secretion, covalently closed circular DNA formation and infectious particle secretion. hNTCP‑expressing PPHs were susceptible to infection with HBV particles purified from pooled HBV‑positive sera, but were poisoned by raw HBV‑positive sera. The use of HBV‑infected hNTCP‑expressing PPHs for viral entry inhibitor screening was revealed to be applicable and reproducible. In conclusion, hNTCP‑expressing PPHs may be valuable tool for investigating HBV infection and antiviral drugs.

Hepatitis B virus (HBV) has four open reading frames (ORFs) of which ORF C is consists of the pre Core and Core genes encodes the Hepatitis B core antigen (HBcAg) and Hepatitis B e antigen (HBeAg). Studies have shown that HBeAg significantly inhibits the NLRP3 inflammasome activation and interleukin-1β (IL-1β) production. However, the role of HBcAg and ORF C proteins (in this paper, ORF C proteins = HBcAg + HBeAg) were remain unclear. Our study aims to assess whether HBcAg and ORF C proteins can affect the NLRP3 inflammasome pathway. Vectors expressing ORF C proteins and HBcAg were designed and transfected into HepG2 cells. And then, cells were stimulated with lipopolysaccharide (LPS). Activation of the NLRP3 inflammasome and the levels of IL-1β and IL-18 were evaluated by Western blot analysis, quantitative reverse-transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and immunofluorescence. The expression of NLRP3 and IL-1β peaked when HepG2 cells were stimulated with 1000 ng/mL LPS for 18 to 24 hours. HBcAg, but not ORF C proteins, promoted LPS-induced NLRP3 inflammasome activation and IL-1β production. These findings provide a novel mechanism on how the HBV causes liver inflammation and may provide insights into the search for new therapeutic strategies., (© 2019 Wiley Periodicals, Inc.)

Nucleos(t)ide analogs (NAs) are widely used in the treatment of hepatitis B virus (HBV) and human immunodeficiency virus (HIV). The mutation L210W of HIV‑1 reverse transcriptase (RT) is one of the six principal mutations which confer in vivo resistance to zidovudine. Due to the similar 3D‑structure and high conservation between HIV‑RT and HBV‑RT, the present study aimed to clarify whether corresponding mutations in HBV may decrease its susceptibility to relevant NAs. Mutations including rtL228C/W, rtL229W and rtL228W/L229W were introduced into a HBV replication competent plasmid by fusion polymerase chain reaction. Replication capacity, HBs/e antigen (Ag) levels and susceptibility to NAs were subsequently analyzed in vitro. Single or combination mutations of rtL228 and rtL229 impaired HBV replication. Decreased HBsAg secretion in the supernatant and production in the cell lysate wasobserved with single rtL229W or in combination with rtL228W, while there was no significant difference between wild‑type and mutant HBV with regard to the level of HBeAg in the supernatant and susceptibility to commonly‑used NAs. Substitution mutations of rtL228 and/or L229 in HBV did not alter the susceptibility of the virus to NAs, although replication and HBsAg secretion were affected.

In our previous work, we found that the expression of ubiquitin-specific protease 18 (USP18), also known as UBP43, is associated with the efficiency of interferon alpha (IFN-α) treatment in patients with chronic hepatitis B (CHB). To elucidate the influence of USP18 on hepatitis B virus (HBV) replication and the mechanism of this activity, we silenced USP18 by introducing short hairpin RNA (shRNA) into Hepg2.2.15 cells. To identify the changed genes and pathways in Hepg2.2.15-shRNA-USP18 cells, we performed a microarray gene expression analysis to compare the Hepg2.2.15 stably expressing USP18-shRNA cells versus control cells using the Affymetrix Human Transcriptome Array (HTA) 2.0 microarrays. Microarray analysis indicated that genes involved in regulation of thyroid hormone signaling pathway, complement, and coagulation cascades, PERK-mediated unfolded protein response, and insulin-like growth factor-activated receptor activity were significantly altered after USP18 knockdown for 72 h. Furthermore, genes involved in hepatocyte proliferation, liver fibrosis, such as cell cycle regulatory gene CCND1, were also altered after USP18 knockdown in Hepg2.2.15 cells. In conclusion, USP18 is critical for regulating the replication of HBV in Hepg2.2.15 cells, which suggest that USP18 may be a candidate target for HBV treatment., (© 2017 Wiley Periodicals, Inc.)

Ubiquitin-specific protease 18 (USP18, also known as UBP43) has both interferon stimulated gene 15 (ISG15) dependent and ISG15-independent functions. By silencing the expression of USP18 in HepG2.2.15 cells, we studied the effect of USP18 on the anti-HBV activity of IFN-F and demonstrated that knockdown of USP18 significantly Inhibited the HBV expression and increased the expression of ISGs. Levels of hepatitis B virus surface antigen (HBsAg), hepatitis B virus e antigen (HBeAg), HBV DNA and intracellular hepatitis B virus core antigen (HBcAg) were dramatically decreased with or without treatment of indicated dose of IFN-F. Suppression of USP18 activated the JAK/STAT signaling pathway as shown by the increased and prolonged expression of phosphorylated signal transducer and activator of transcription 1 (p-STAT1) in combination with enhanced expression of several interferon stimulated genes (ISGs). Our results indicated that USP18 modulates the anti-HBV activity of IFN-F via activation of the JAK/STAT signaling pathway in Hepg2.2.15 cells.

Cellular microRNAs (miRNAs) are able to influence hepatitis B virus (HBV) replication directly by binding to HBV transcripts or indirectly by targeting cellular factors. Here, we investigate the effect of epigenetically regulated miR-449a on HBV replication and the underlying mechanisms. miR-449a expression was lower in human hepatocellular carcinoma (HCC) cells than in primary hepatocytes and could be induced by trichostatin A. Ectopic miR-449a expression in HCC cells strongly enhanced HBV replication, transcription, progeny virions secretion, and antigen expression in a dose-dependent manner. miR-449a directly targeted cAMP-responsive element binding protein 5 (CREB5), which in turn induced the expression of farnesoid X receptor α (FXRα), a transcription factor that facilitates HBV replication. CREB5 knockdown and overexpression demonstrated that it is a negative regulator of HBV replication. Additionally, miR-449a overexpression inhibited proliferation, caused cell cycle arrest, and promoted HCC cell differentiation. The results indicated that epigenetically regulated miR-449a targets CREB5 to increase FXRα expression, thereby promoting HBV replication and gene expression. Our findings provide a new understanding of the role of miRNAs in HBV replication.

Background and Aims: Previous studies examining the relationship between hepatitis B virus (HBV) genotype B and C and response to interferon therapy in Hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients have yielded conflicting results. We aim to summarize data to reach firm conclusions on the role of HBV genotype B and C in response to interferon therapy., Methods: PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched for relevant articles published up to March 2013. Odds ratios (ORs) and 95% confidence intervals (CI) were calculated by fixed- or random-effects models. Heterogeneity, sensitivity analysis, and publication bias were also assessed., Results: Fifteen studies were identified. All studies except for those evaluating the rate of end-of-treatment HBeAg seroconversion exhibited significant heterogeneity. There were significant differences in rates of end-of-treatment alanine aminotransferase (ALT) normalization, HBV DNA negative, and HBeAg seroconversion between the genotype B and genotype C groups, but not in HBeAg clearance. The pooled results showed higher rates of sustained ALT normalization (OR = 2.24, 95%CI 1.53-3.27), HBV DNA negative (OR = 2.60, 95%CI 1.65-4.12), HBeAg clearance (OR = 2.13, 95%CI 1.29-3.52) and HBeAg seroconversion (OR = 1.95, 95%CI 1.27-2.98) in patients with genotype B than those with genotype C. The sensitivity analysis did not alter the effects observed in the primary analysis. There was no evidence of publication bias except for HBeAg clearance rate., Conclusions: The results of the current meta-analysis indicate that HBV genotype B patients receiving interferon therapy respond better to treatment compared with genotype C patients, but this needs to be further examined., (© 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Interferon (IFN)-α is able to stimulate many cellular genes and inhibit the replication of various viruses. However, it is unknown whether some IFN-stimulated genes (ISGs) specifically inhibit hepatitis B virus (HBV) replication. Therefore, we attempted to identify ISGs with antiviral activities against HBV. Knockdown of IFN-induced proteins with tetratricopeptide repeats 1 and 2 (IFIT1 and IFIT2) in HepG2.2.15 led to markedly increased HBV replication. Consistently, this effect was verified by transient transfection with a replication-competent HBV clone in HepG2 and Huh7. However, IFN-α stimulation could override the knockdown by siRNAs and enhance the expression of IFIT1 and IFIT2, leading to reduced HBV replication. Silencing of IFIT1 or IFIT2 decreased the expression of the corresponding genes while other ISGs like MxA were not affected. Northern blot analysis showed that IFIT1 and IFIT2 knockdown slightly increased the levels of HBV 3.5, 2.4 and 2.1 kb transcripts, while IFIT1 and IFIT2 overexpression did not change their levels. Consistently, the reporter assays with HBV promoters demonstrated that IFIT1 and IFIT2 differentially but only modestly regulated HBV promoter activity. Thus, IFIT1 and IFIT2 contribute significantly to the regulation of HBV replication, likely at both transcriptional and posttranscriptional steps., (Copyright © 2013 S. Karger AG, Basel)

Hepatitis B virus (HBV) is a persistent pathogen that causes acute and chronic necroinflammatory liver disease and is attributable to ~1 million deaths per year. In the present study, a conventional murine model was introduced based on the hydrodynamic injection of engineered replication‑competent HBV DNA into the tail veins of C57BL/6 mice. In a previous study, nine in‑frame ATG (start) codons in the S open reading frame (S1‑S9) were analyzed. The highly conserved ATG S5 was mutated to ACG by T378C, which led to the substitution sM75T and inhibition of the production and secretion of the hepatitis B surface antigen (HBsAg), and subsequent inhibition of HBV replication. In the present study, T378C was introduced into the pAAV‑HBV1.3 plasmid and was confirmed to affect HBsAg production and secretion, and HBV replication in vivo, which was in agreement with the previous in vitro results. Furthermore, the murine model was improved by co‑injection of the replication‑competent HBV plasmid DNA with Lipofectamine 2000 (LP). In this model, LP not only significantly enhanced HBV replication in mice, but also upregulated the expression of HBsAg and the hepatitis B core antigen. The current modified murine model was superior to the conventional murine HBV model based on HBV challenge by hydrodynamic injection.

Background: Quantification of hepatitis B surface antigen (HBsAg) in serum may be of clinical importance in predicting treatment response towards interferon α (IFNα)., Aims: To explore the predictive role of serum quantitative HBsAg in predicting treatment response towards IFNα-1b in hepatitis B e antigen-positive chronic hepatitis B patients., Methods: Seventy patients received 5 MU of IFNα-1b three times weekly for 48 weeks; the quantification of HBsAg was carried out at baseline, weeks 12, 24, 36, and 48 during treatment. At the end of treatment, the predictive role of quantitative HBsAg in predicting treatment response towards IFNα-1b was evaluated., Results: From weeks 12 to 48, the serum hepatitis B virus DNA and HBsAg levels were positively correlated; the HBsAg levels were lower in responders than those in nonresponders and the difference was statistically significant (P<0.05). The HBsAg cutoff of 6109.01 IU/ml in serum at week 24 had a positive predictive value of 37.5% and a negative predictive value of 94.7%, and with an area under the receiver operating characteristic curve of 0.816., Conclusion: On-treatment, serum HBsAg had a high predictive value to predict treatment response towards IFNα-1b.

Chronic hepatitis B virus (CHB) infection is a major cause of cirrhosis and hepatocellular carcinoma. Nucleoside analogs (NAs) are popularly used to treat chronic hepatitis B virus (HBV) infections; however, the anti-HBV effect is attenuated by drug-resistant viral mutations selected during long-term antiviral therapy. The timely analysis of drug-resistance mutations is essential in order to adjust treatment regimes. In this study, a T1699C substitution was introduced into the x gene of pHBV1.3 to generate an additional XhoI site, termed pHBV1.3‑XhoI, which is a nonsense mutation and does not influence protein expression, HBV replication ability, or NA susceptibility. Based on co-transfection with weak or non-replicative HBV plasmids and pHBV1.3-XhoI or pHBV1.3 and -XhoI-P-null plasmids into hepatocellular carcinoma cells, PCR was used to amplify 1176‑bp segments of T/C1699 using the isolated HBV encapsulated DNA as a template, modified by XhoI digestion and subjected to agarose gel electrophoresis. Different bands composed of different virions were used to distinguish the replication capacities of the plasmids. Our results demonstrated no significant effects when different virions co-existed. A novel resistance test method was developed by co-transfection with pHBV1.3-XhoI and -rtL180M/M204V and treatment with various NA concentrations. Different bands composed of pHBV1.3-XhoI or -rtL180M/M204V were used to distinguish NA susceptibility. The bands composed of pHBV1.3 were more sharply reduced by lamivudine (LMV) than -rtL180M/M204V. The data demonstrate that the method established in our study may be used for the analysis of drug-resistant phenotypes at the cellular level.

Long term antiviral therapy with nucleoside/nucleotide analogs have been routinely used to treat chronic hepatitis B virus (HBV) infection but may lead to the emergence of drug-resistant viral mutants. However, the HBV resistance mutations for tenofovir (TDF) remain controversial. It is speculated that the genetic barrier for TDF resistance may be high for HBV. We asked whether selected amino acid substitutions in HBV polymerase may reduce susceptibility to TDF. A series of amino acids in HBV polymerase were selected based on bioinformatics analysis for mutagenesis. The replication competence and susceptibility to TDF of the mutated HBV clones were determined both in vitro and in vivo. nineteen mutations in HBV polymerase were included and impaired the replication competence of HBV genome in different degrees. The mutations at rtL77F (sS69C), rtF88L (sF80Y), and rtP177G (sR169G) also significantly affected HBsAg expression. The HBV mutants with rtP177G and rtF249A were found to have reduced susceptibility to TDF in vitro with a resistance index of 2.53 and 12.16, respectively. The testing in in vivo model based on the hydrodynamic injection revealed the antiviral effect of TDF against wild type and mutated HBV genomes and confirmed the reduced the susceptibility of mutant HBV to TDF., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The hepatitis C virus (HCV) core protein is a multifunctional protein that can interfere with the induction of an immune response. It has been reported that the HCV core protein inhibits HBV replication in vitro. In this study, we test the effect of the HCV core gene on the priming of the immune response to hepatitis B surface antigen (HBsAg) and on the replication of HBV in vivo. Our results showed that the full-length HCV core gene inhibits the induction of an immune response to the heterogeneous antigen, HBsAg, at the site of inoculation when HCV core (pC191) and HBsAg (pHBsAg) expression plasmids are co-administered as DNA vaccines into BALB/c mice. The observed interference effect of the HCV core occurs in the priming stage and is limited to the DNA form of the HBsAg antigen, but not to the protein form. The HCV core reduces the protective effect of the HBsAg when the HBsAg and the HCV core are co-administered as vaccines in an HBV hydrodynamic mouse model because the HCV core induces immune tolerance to the heterogeneous HBsAg DNA antigen. These results suggest that HCV core may play an important role in viral persistence by the attenuation of host immune responses to different antigens. We further tested whether the HCV core interfered with the priming of the immune response in hepatocytes via the hydrodynamic co-injection of an HBV replication-competent plasmid and an HCV core plasmid. The HCV core inhibited HBV replication and antigen expression in both BALB/c (H-2d) and C57BL/6 (H-2b) mice, the mouse models of acute and chronic hepatitis B virus infections. Thus, the HCV core inhibits the induction of a specific immune response to an HBsAg DNA vaccine. However, HCV C also interferes with HBV gene expression and replication in vivo, as observed in patients with coinfection.

Naturally occurring mutations in surface proteins of Hepatitis B virus (HBV) usually result in altered hepatitis B surface antigen (HBsAg) secretion efficiency. In the present study, we reported two conserved residues, M75 and M103 with respect to HBsAg, mutations of which not only attenuated HBsAg secretion (M75 only), but also suppressed HBV genome replication without compromising the overlapping p-gene product. We also found M75 and M103 can initiate truncated surface protein (TSPs) synthesis upon over-expression of full-length surface proteins, which may possibly contribute to HBV genome replication. However, attempts to rescue replication-defective HBV mutant by co-expression of TSPs initiated from M75 or M103 were unsuccessful, which indicated surface proteins rather than the putative TSPs were involved in regulation of HBV genome replication.

Hepatitis B virus (HBV) infection remains a major global threat to human health worldwide. Recently, the Chinese medicines with antiviral properties and low toxicity have been a concern. In our previous study, Eupolyphaga sinensis Walker polysaccharide (ESPS) has been isolated and characterized, while its antiviral effect on HBV remained unclear. The anti-HBV activity of ESPS and its regulatory pathway were investigated in vitro and in vivo. The results showed that ESPS significantly inhibited the production of HBsAg, HBeAg, and HBV DNA in the supernatants of HepG2.2.15 in a dose-dependent manner; HBV RNA and core protein expression were also decreased by ESPS. The in vivo studies using HBV transgenic mice further revealed that ESPS (20 and 40 mg/kg/2 days) significantly reduced the levels HBsAg, HBeAg, and HBV DNA in the serum, as well as HBV DNA and HBV RNA in mice liver. In addition, ESPS activated the Toll-like receptor 4 (TLR4) pathway; elevated levels of IFN-β, TNF-α, and IL-6 in the serum were observed, indicating that the anti-HBV effect of ESPS was achieved by potentiating innate immunity function. In conclusion, our study shows that ESPS is a potential anti-HBV ingredient and is of great value in the development of new anti-HBV drugs. [ABSTRACT FROM AUTHOR]

Background & Aims: Hepatitis B virus (HBV) infection is the most critical factor underlying liver cirrhosis and hepatocellular carcinoma worldwide. IL‐1β and IL‐18, generated by activation of the inflammasome/caspase‐1 signaling pathway, play important roles in the control and clearance of HBV. However, the specific relationship between the inflammasome response and IFN‐α resistance or viral persistence is yet to be established. Methods: Blood samples of patients and supernatant fractions of HBV cell lines were collected for analysis and the effects on inflammasome activation and IL‐1β production evaluated via enzyme‐linked immunosorbent assay (ELISA), western blot, quantitative RT‐PCR and immunofluorescence. Results: IL‐1β and IL‐18 levels produced in sera of IFN‐α non‐responders were significantly lower than those of responders and normal donors. Additionally, expression of IL‐1β and inflammasome components was decreased in peripheral blood mononuclear cells (PBMC) of non‐responders, compared with those of responders. In vitro experiments on HepG2, HepG2.2.15 and HepAD38 cell lines showed that HBV induces a significant decrease in IL‐1β production through inhibiting activation of the NF‐κB signaling and inflammasome/caspase‐1 pathways. And hepatitis B virus polymerase (HBV‐Pol) appeared crucial for these inhibitory effects of HBV. Conclusion: IL‐1β production is suppressed in HBV carriers and IFN‐α non‐responders. HBV induces a significant decrease in IL‐1β production through inhibiting the NF‐κB signaling and inflammasome pathways, for which HBV‐Pol is a crucial requirement. Trial approval number: 20 173 402. [ABSTRACT FROM AUTHOR]

Background: Interferon-α is approved as one of the main therapeutic treatments for chronic hepatitis B virus infection, but only a small number of patients achieve sustained virological response. The molecular mechanisms underlying IFN-α resistance in those patients who do not respond remain elusive. Previous work in our laboratory identified the pre-activation of IFN signaling leading to increased expression of a subset of interferon stimulated genes in the pretreatment liver tissues of chronic HBV infected patients correlated with treatment non-response. Aims: We studied the cell-type specific gene expression of interferon stimulated genes in the liver of chronic HBV infected patients and the cellular basis of the phenotype through ISG15 and MxA protein expression. Methods: Immunohistochemical analysis was used to detect the expression of ISG15 and MxA protein in the pretreatment liver tissues of chronic HBV infected patients and the expression patterns were correlated with treatment outcomes. Results: In the non-responders, ISG15 and MxA protein expression in the pretreatment liver tissues was more pronounced in hepatocytes while in the responders, ISG15 and MxA protein expression was more focused in macrophages. ISG15 and MxA proteins were occasionally expressed in hepatocytes in normal livers. Conclusion: There were significant differences in the cell-type specific protein expression of ISG15 and MxA in the pretreatment liver tissues of chronic HBV infected patients between treatment responders and non-responders. An easy prediction method based on immunohistochemical stains of a subset of interferon stimulated genes may be developed to predict treatment outcomes of IFN therapy in chronic HBV infected patients. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) infection represents one of the most critical health problems worldwide. Tripartite motif protein 38 (TRIM38) is an interferon-stimulated gene (ISG) that inhibits various DNA and RNA viruses.In this study, we found a mechanistic correlation between TRIM38 expression levels and the efficacy of HBV infection and IFN-α therapy in patients with CHB. TRIM38 was highly induced by IFN-alpha (IFN-α) in vivo and in vitro. TRIM38 overexpression inhibited HBV replication and gene expression in HepG2 and HepG2.2.15 cells, whereas knockdown of TRIM38 increased these processes. Further experiments indicated that TRIM38 protein enhanced the antiviral effect of IFN-α by enhancing the expression of antiviral proteins. A prospective study revealed high TRIM38 levels in peripheral blood PBMCs were from early responders, and increased TRIM38 expression correlated with a better response to PEG-IFN-α therapy. Taken together, our study suggests that TRIM38 plays a vital role in HBV replication and gene expression. • TRIM38 can inhibit HBV replication and gene expression in vitro and in vivo. • TRIM38 expression was associated with the treatment response to PEG-IFN-α therapy. • TRIM38 protein enhanced the antiviral effect of IFN-α by enhancing the expression of antiviral proteins. [ABSTRACT FROM AUTHOR]

Chronic hepatitis B virus (HBV) infection is a worldwide public health problem that causes significant liver-related morbidity and mortality. In our previous study, Strongylocentrotus nudus eggs polysaccharide (SEP), extracted from sea urchins, had immunomodulatory and antitumor effects. Whether SEP has anti-HBV activity is still obscure. This study demonstrated that SEP decreased the secretion of hepatitis B surface antigen (HBsAg) and e antigen (HBeAg), as well as the replication and transcription of HBV both in vitro and in vivo. Immunofluorescence and immunohistochemistry results showed that the level of HBV core antigen (HBcAg) was clearly reduced by SEP treatment. Mechanistically, RT-qPCR, western blot, and confocal microscopy analysis showed that SEP significantly increased the expression of toll-like receptor 4 (TLR4) and co-localization with TLR4. The downstream molecules of TLR4, including NF-κb and IRF3, were activated and the expression of IFN-β, TNF-α, IL-6, OAS, and MxA were also increased, which could suppress HBV replication. Moreover, SEP inhibited other genotypes of HBV and hepatitis C virus (HCV) replication in vitro. In summary, SEP could be investigated as a potential anti-HBV drug capable of modulating the innate immune. The schematic of the pathway for SEP in the antiviral process. SEP binds to the TLR4 on the cell surface and upregulates TLR4 expression, triggering the interferon signaling cascade and the inflammatory signaling pathway to exert an indirect antiviral effect. [Display omitted] [ABSTRACT FROM AUTHOR]