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Chronic hepatitis B is linked with considerable liver-related morbidity and mortality globally. Human leukocyte antigen (HLA) polymorphisms affect the susceptibility and outcome of many immune-mediated diseases and infections. Our aim was to study the impact of HLA alleles on HVB-infected individuals in a Greek population. In total, 107 patients with chronic HBV infection (cHBV group) and 101 with spontaneous clearance (SC-group) of hepatitis B surface antigen (HBsAg) were genotyped for HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 loci by single-specific primer polymerase chain reaction (PCR-SSP). The HLA alleles’ frequencies were compared between the two patient groups and healthy individuals from the North Greece Bone Marrow Donor Registry (14506 samples). We found a significantly increased frequency of HLA-C*01 and HLA-DRB1*16 alleles in the cHBV group versus the SC-group. The frequency of HLA-A*01, HLA-B*08, HLA-C*01, HLA-C*08, HLA-DRB1*03, and HLA-DQB1*05 alleles was significantly higher in cHBV patients versus healthy individuals, while the frequency of the HLA-B*38 allele was significantly lower. Our study showed an association of specific HLA alleles with either susceptibility or protection against chronic HBV infection.

The immunopathogenesis of chronic hepatitis B (CHB) with unclear immune phases hinders functional cure. For highly infectious HBeAg-positive (HBeAg + ) patients where functional cure is unattainable, achieving sustained HBeAg seroconversion constitutes the key therapeutic objective. This study used single-cell sequencing (scRNA-seq) to analyze B-cell subsets dynamics during HBeAg seroconversion and their roles in restricting HBsAg seroconversion. ScRNA-seq datasets (GSE182159, GSE234241) were retrieved from the GEO database, comprising 67 peripheral blood/liver samples. After batch correction and integration, compared with the two HBeAg + phases, patients with HBeAg-negative (HBeAg⁻) chronic HBV infection show opposite distribution trends of naive and memory B cells in peripheral blood and liver. Compared with healthy controls and chronic resolved (CR) cases, the HBeAg⁻ chronic HBV infection and HBeAg⁻ groups showed decreased plasma cell proportions in both peripheral blood and liver along with increased hepatic non-switched and switched memory B cells. Functional analysis indicates that B cell subsets in the HBeAg + group may present more severe metabolic dysfunctions, epigenetic abnormalities, as well as signaling and differentiation defects compared to the HBeAg⁻ group, suggesting a potential pivotal role of B cell subsets in HBeAg seroconversion. Moreover, relative to the CR group, B cell subsets in the HBeAg⁻ group are likely to exhibit more profound energy metabolic impairment and aberrant immune activation, which may consequently facilitate the persistence of HBV infection. B-cell subsets may play a pivotal role in HBeAg seroconversion, and their altered proportions and functional defects may further contribute to the persistence of HBV infection.

To better define the mechanism(s) likely responsible for viral clearance during hepatitis B virus (HBV) infection, viral clearance was studied in a panel of immunodeficient mouse strains that were hydrodynamically transfected with a plasmid containing a replication-competent copy of the HBV genome. Neither B cells nor perforin were required to clear the viral DNA transcriptional template from the liver. In contrast, the template persisted for at least 60 days at high levels in NOD/Scid mice and at lower levels in the absence of CD4⁺ and CD8⁺ T cells, NK cells, Fas, IFN-gamma (IFN-γ), IFN-alpha/beta receptor (IFN-α/βR1), and TNF receptor 1 (TNFR1), indicating that each of these effectors was required to eliminate the transcriptional template from the liver. Interestingly, viral replication was ultimately terminated in all lineages except the NOD/Scid mice, suggesting the existence of redundant pathways that inhibit HBV replication. Finally, induction of a CD8⁺ T cell response in these animals depended on the presence of CD4⁺ T cells. These results are consistent with a model in which CD4⁺ T cells serve as master regulators of the adaptive immune response to HBV; CD8⁺ T cells are the key cellular effectors mediating HBV clearance from the liver, apparently by a Fas-dependent, perforin-independent process in which NK cells, IFN-γ, TNFR1, and IFN-α/βR play supporting roles. These results provide insight into the complexity of the systems involved in HBV clearance, and they suggest unique directions for analysis of the mechanism(s) responsible for HBV persistence.

Persistent hepatitis B virus (HBV) infection results in chronic liver diseases that may progress to chronic hepatitis, liver cirrhosis, and subsequent hepatocellular carcinoma. Previous studies demonstrated that adaptive immunity, in particular CD8 T cells, is critical in HBV elimination. Recent studies have revealed a distinct tissue-localized T cell lineage, tissue-resident memory (TRM) cells, that is crucial for protective immunity in peripheral tissues. In this study, we showed that treatment with an anti-asialo GM1 (ASGM1) antibody (Ab), which depletes NK cells, led to impairment of HBV clearance in a mouse animal model. Unexpectedly, the ability to clear HBV was not significantly impaired in NFIL3 KO mice, which are deficient in NK cells, implying that other non-NK ASGM1-positive immune cells mediate HBV clearance. We isolated intrahepatic ASGM1-positive cells from NFIL3 KO mice and analyzed the immune phenotype of these cells. Our results demonstrated a distinct population of CD44+ LFA-1hi CD8 T cells that were the major intrahepatic ASGM1-positive immune cells in NFIL3 KO mice. Importantly, transcriptome analysis revealed that these ASGM1-positive CD8 T cells had distinct gene profiles and shared a similar core gene signature with TRM cells. In addition to both transcriptional and phenotypic liver residency characteristics, ASGM1-positive CD8 T cells were able to home to and be retained in the liver after adoptive transfer. Taken together, our study results indicate that these ASGM1-positive liver-resident CD8 T cells are the major effector immune cells mediating anti-HBV immunity.

Chronic infection by hepatitis B virus (HBV) is associated with high risks of liver fibrosis, cirrhosis and hepatocellular carcinoma. In mouse models of HBV persistence, interleukin 21 (IL-21) has been identified as a potent inducer of viral clearance. Strict hepatotropism makes recombinant HBV (rHBV) vectors ideal for liver-targeting gene delivery. Previously, we established an rHBV vector termed 5c3c, which is highly replicative by itself, but requires HBV envelope proteins provided to produce virions. 5c3c-based rHBV virions are capable of delivering cargo gene expression driven by HBV Sp1 promoter into infected hepatocytes. In this work, we explore the feasibility of using 5c3c-derived rHBV for liver-specific delivery of IL-21 as treatment of chronic HBV infection. 5c3c-derived rHBV replicons harboring mouse or human IL-21 genes (termed 5c3c-mIL-21 and 5c3c-hIL-21 respectively) were constructed and then tested for the production of rHBV virions and . 5c3c-mIL-21's anti-HBV effects were determined in chronic HBV mouse model. Furthermore, superinfection by rHBV virions was analysed using HBV-infected HepG2/NTCP cells and human liver chimeric mice. 5c3c-mIL-21 and 5c3c-hIL-21 were efficiently replicative and produced enveloped virions when provided with envelope proteins, both and . In mouse model of HBV persistence, IL-21 expressed from injected 5c3c-mIL-21 replicon induced complete viral clearance. 5c3c-mIL-21 and 5c3c-hIL-21 virions could infect HepG2/NTCP cells and engender sustained IL-21 expression. Most importantly, IL-21-expressing rHBV virions could superinfect HBV-infected HepG2/NTCP cells and human hepatocytes in human liver chimeric mice, and engender sustained IL-21 expression and rHBV production. These data suggest the high potential of 5c3c-derived IL-21-expressing rHBV as a novel therapeutic against chronic HBV infection.

Evidence shows people living with CHB even with a normal ALT (40U/L as threshold) suffer histological disease and there is still little research to evaluate the potential benefit of antiviral benefits in them. We retrospectively examined 1352 patients who underwent liver biopsy from 2017 to 2021 and then obtained their 1-year follow-up data to analyze. ALT levels were categorized into high and low, with thresholds set at >29 for males and >15 for females through Youden's Index. The high normal ALT group showed significant histological disease at baseline (56.43% 43.82%, p< 0.001), and better HBV DNA clearance from treatment using PSM (p=0.005). Similar results were obtained using 2016 AASLD high normals (male >30, female >19). Further multivariate logistic analysis showed that high normal ALT (both criterias) was an independent predictor of treatment (OR 1.993, 95% CI 1.115-3.560, p=0.020; OR 2.000, 95% CI 1.055-3.793, p=0.034) Both of the models had higher AUC compared with current scoring system, and there was no obvious difference between the two models (AUC:0.8840 0.8835). Male >30 or female >19 and Male >29 or female>15 are suggested to be better thresholds for normal ALT. Having a high normal ALT in CHB provides a potential benefit in antiviral therapy.

It is the first time that mRNA-LNPs have been used to express anti-HBsAg antibodies (G12-scFv, G12-scFv-Fc, and G12-IgG). G12-scFv-Fc- and G12-IgG-encoding mRNA-LNPs exerted a sustained effect on HBsAg serum clearance in the adeno-associated virus (AAV)/HBV mouse model with persistent HBsAg expression. Hepatitis B virus (HBV) infection is a serious global health issue with more than 250 million chronic carriers. It causes liver diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Persistent suppression of the HBV surface antigen (HBsAg) is necessary for a functional cure of chronic hepatitis B (CHB) virus infection. However, this can hardly be achieved with currently approved drugs. Antibody treatment against HBsAg has shown promise in restoring HBV-specific immune responses and promoting HBV cure. To achieve long-lasting HBsAg suppression, we used an advanced mRNA drug to encode the genes of three anti-HBsAg antibodies, G12-scFv, G12-scFv-Fc, and G12-IgG. Antibody-encoding mRNA-lipid nanoparticles (LNPs), mL (G12-scFv-Fc) and mL (G12-IgG), substantially reduced serum HBsAg levels in treated mice within 30 days after a single dose. In contrast, exogenous antibodies lost effect on reducing HBsAg or HBV DNA levels 9 days postadministration. The high affinity of anti-HBsAg antibodies and the adjuvant activity of mRNA-LNPs resulted in long-term HBsAg seroclearance, which could contribute to the reestablishment of the immune system in HBV carriers. These findings highlight the great potential of antibody-encoding mRNA molecules against CHB infection. IMPORTANCE It is the first time that mRNA-LNPs have been used to express anti-HBsAg antibodies (G12-scFv, G12-scFv-Fc, and G12-IgG). G12-scFv-Fc- and G12-IgG-encoding mRNA-LNPs exerted a sustained effect on HBsAg serum clearance in the adeno-associated virus (AAV)/HBV mouse model with persistent HBsAg expression. These findings may provide a new design of combination therapy for functional cure of HBV. For example, this strategy could provide an alternative for antibodies in “sandwich” therapy and further enhance the immunization properties of the therapy. Overall, mRNA therapeutics are promising for treatment of infectious diseases because of their rapid development, economic value, and simplicity.

Background The complement system (CS) is central to antiviral defence, yet many viruses subvert it to escape clearance. Complement-component C3 is the key effector molecule of CS that plays diverse roles in pathogen elimination, inflammation and immune responses, but its regulation during chronic HBV infection (CHI) remains poorly understood. This study examined the mechanisms governing C3 expression in hepatocytes and immune cells during CHI and evaluated the impact of altered C3 levels on viral persistence and host immunity. Methods C3 expression was evaluated in blood and liver-tissue samples from patients with CHI and healthy controls using ELISA and RT-PCR. HBV-transfected hepatoma cells were used to examine epigenetic regulation of C3, including promoter methylation, histone deacetylation, and transcription factor phosphorylation. Autophagy-related functions of C3 were assessed by immunofluorescence. Flow cytometry was used to determine the intracellular C3 levels in immune cells of HBV-infected patients and the influence of viral and host factors on C3 expression. Additionally, cytokine production by immune cells and the modulating effect of recombinant C3a on these cytokines was studied. The effect of Tenofovir therapy on C3 concentration was also evaluated. Results C3 level was found to be significantly diminished in sera and liver-tissues of HBV-infected patients and HBV-expressing hepatoma cells relative to controls. HBX suppressed C3 transcription by restricting the availability of the crucial transcription factor, C/EBPβ through its promoter hypermethylation and by enhancing histone deacetylation at C3-promoter including C/EBPβ binding-sites whereas, HBV surface proteins (HBS) further blocked C/EBPβ phosphorylation essential for transcription. Functionally, C3 deficiency disrupted autophagosome-lysosome fusion and prevented autophagic degradation of viral proteins, leading to enhanced HBV release. Reduced intracellular C3 was noted in monocytes and virus-specific T cells of HBV-infected patients that could be attributed to exposure to HBS and cytokines (IL-4/IL-1β). The decline in C3 skewed the immune responses toward an anti-inflammatory phenotype with diminished pro-inflammatory activities, which were reversed by recombinant C3a. One-year of Tenofovir therapy partially restored serum but not immune-cell C3 levels. Conclusion HBV downregulates C3 through epigenetic and signalling mechanisms, facilitating viral persistence and dampening antiviral immunity. Targeting complement regulation may represent a novel therapeutic strategy in CHI. Graphical abstract

The immunopathogenesis and molecular mechanisms involved during a hepatitis B virus (HBV) infection have made the approaches for research complex, especially concerning the patients’ responses in the course of the early acute stage. The study of molecular bases involved in the viral clearance or persistence of the infection is complicated due to the difficulty to detect patients at the most adequate points of the disease, especially in the time lapse between the onset of the infection and the viral emergence. Despite this, there is valuable data obtained from animal and in vitro models, which have helped to clarify some aspects of the early immune response against HBV infection. The diversity of the HBV (genotypes and variants) has been proven to be associated not only with the development and outcome of the disease but also with the response to treatments. That is why factors involved in the virus evolution need to be considered while studying hepatitis B infection. This review brings together some of the published data to try to explain the immunological and molecular mechanisms involved in the different stages of the infection, clinical outcomes, viral persistence, and the impact of the variants of HBV in these processes.

Background Hepatitis B virus (HBV) chronic infection affects up to 240 million people in the world and it is a common cause of cirrhosis and hepatocellular carcinoma (HCC). HBV covalently closed circular DNA (cccDNA) plays an essential role in HBV persistence and replication. Current pharmacological treatment with nucleos(t)ide analogues (NA) may suppress HBV replication with little or no impact on cccDNA, hence lifelong treatment is required in the vast majority of patients. Clearances of intrahepatic cccDNA and/or HBsAg are critical endpoints for future antiviral therapy in chronic HBV. Recent promising developments targeting different molecular HBV life cycle steps are being pre-clinically tested or have moved forward in early clinical trials. Methods We review the current state of the art of these pharmacological developments, mainly focusing on efficacy and safety results, which are expected to lay the ground for future HBV eradication. An inclusive literature search on new treatments of HBV using the following electronic databases: Pubmed/MEDLINE, AMED, CINAHL and the Cochrane Central Register of Controlled Trials. Full-text manuscripts and abstracts published over the last 12 years, from 2005 to March 2011 were reviewed for relevance and reference lists were crosschecked for additional applicable studies regarding new HBV antiviral treatment. Results HBV entry inhibitors, HBV core inhibitors, HBV cccDNA transcripts RNA interference, HBV cell apoptosis inducers, HBV RNA, viral proteins and DNA knock down agents, HBV release inhibitors, anti-sense nucleosides, exogenous interferon stimulation, interferon response stimulation and HBV therapeutic vaccines were reviewed. Conclusion This review will provide readers with an updated vision of current and foreseeable therapeutic developments in chronic hepatitis B.