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Frontiers in Immunology 2023Despite treatment, hepatitis B surface antigen (HBsAg) persists in patients with chronic hepatitis B (CHB), suggesting the likely presence of the virus in the body. CD8...
Despite treatment, hepatitis B surface antigen (HBsAg) persists in patients with chronic hepatitis B (CHB), suggesting the likely presence of the virus in the body. CD8 T cell responses are essential for managing viral replication, but their effect on HBsAg levels remains unclear. We studied the traits of activated CD8 T cells and HBV-specific CD8 T cells in the blood of CHB patients undergoing nucleos(t)ide analog (NUC) therapy. For the transcriptome profiling of activated CD8 T cells in peripheral blood mononuclear cells (PBMCs), CD69 CD8 T cells were sorted from six donors, and single-cell RNA sequencing (scRNA-seq) analysis was performed. To detect HBV-specific CD8 T cells, we stimulated PBMCs from 26 donors with overlapping peptides covering the HBs, HBcore, and HBpol regions of genotype A/B/C viruses, cultured for 10 days, and analyzed via multicolor flow cytometry. scRNA-seq data revealed that CD8 T cell clusters harboring the transcripts involved in the cytolytic functions were frequently observed in donors with high HBsAg levels. Polyfunctional analysis of HBV-specific CD8 T cells utilized by IFN-γ/TNFα/CD107A/CD137 revealed that HBcore-specific cells exhibited greater polyfunctionality, suggesting that the quality of HBV-specific CD8 T cells varies among antigens. Moreover, a subset of HBcore-specific CD8 T cells with lower cytolytic potential was inversely correlated with HBsAg level. Our results revealed a stimulant-dependent qualitative difference in HBV-specific CD8 T cells in patients with CHB undergoing NUC therapy. Hence, the induction of HBcore-specific CD8 T cells with lower cytolytic potential could be a new target for reducing HBsAg levels.
Topics: Humans; Hepatitis B Surface Antigens; CD8-Positive T-Lymphocytes; Hepatitis B virus; Leukocytes, Mononuclear; Hepatitis B, Chronic
PubMed: 37920475
DOI: 10.3389/fimmu.2023.1257113 -
Gastroenterology Dec 2023
Topics: Humans; Hepatitis, Chronic; Lipopeptides; Hepatitis Delta Virus; Antiviral Agents; Hepatitis B virus
PubMed: 37178738
DOI: 10.1053/j.gastro.2023.05.007 -
Hepatology International Oct 2023
Topics: Humans; Hepatitis B, Chronic; Hepatitis B Surface Antigens; Immunity; Hepatitis B virus; Hepatitis B
PubMed: 37369910
DOI: 10.1007/s12072-023-10546-5 -
Nature Reviews. Gastroenterology &... Sep 2023
Topics: Humans; Antiviral Agents; Hepatitis B virus; Hepatitis D, Chronic; Hepatitis Delta Virus; Lipopeptides
PubMed: 37553498
DOI: 10.1038/s41575-023-00834-8 -
Nature Structural & Molecular Biology Mar 2024Hepatitis B virus (HBV), a leading cause of developing hepatocellular carcinoma affecting more than 290 million people worldwide, is an enveloped DNA virus...
Hepatitis B virus (HBV), a leading cause of developing hepatocellular carcinoma affecting more than 290 million people worldwide, is an enveloped DNA virus specifically infecting hepatocytes. Myristoylated preS1 domain of the HBV large surface protein binds to the host receptor sodium-taurocholate cotransporting polypeptide (NTCP), a hepatocellular bile acid transporter, to initiate viral entry. Here, we report the cryogenic-electron microscopy structure of the myristoylated preS1 (residues 2-48) peptide bound to human NTCP. The unexpectedly folded N-terminal half of the peptide embeds deeply into the outward-facing tunnel of NTCP, whereas the C-terminal half formed extensive contacts on the extracellular surface. Our findings reveal an unprecedented induced-fit mechanism for establishing high-affinity virus-host attachment and provide a blueprint for the rational design of anti-HBV drugs targeting virus entry.
Topics: Humans; Hepatitis B virus; Hepatocytes; Protein Binding; Virus Attachment; Peptides; Symporters; Virus Internalization
PubMed: 38233573
DOI: 10.1038/s41594-023-01191-5 -
Environmental Science and Pollution... Sep 2023Cadmium, a common metal, is an environmental contaminant that is hepatotoxic and immunotoxic. Cadmium exposure may affect hepatitis B immunity. The purpose of this study...
Cadmium, a common metal, is an environmental contaminant that is hepatotoxic and immunotoxic. Cadmium exposure may affect hepatitis B immunity. The purpose of this study was to assess the association between cadmium exposure and hepatitis B serology in the US population and to develop a model to predict susceptibility of hepatitis B. The study included 50,588 individuals in the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2016. Univariate and multivariate logistic regression and dose-response curves were used to evaluate the relationship between cadmium exposure and hepatitis B serology. Through multivariate logistic regression results, a predictive model was established, and relevant indicators were used to verify the clinical value of the model and evaluate prognostic value of serum cadmium concentration in patients with hepatitis B. We selected 5989 (≥ 6 years old) participants. Univariate logistic regression analysis showed that gender (aOR = 0.7192, 95% CI = 0.6492-0.7968), age (aOR = 1.030, 95% CI = 1.026-1.033), race (aOR = 0.8974, 95% CI = 0.8591-0.9374), poverty ratio (aOR = 1.042, 95% CI = 0.9872-1.101), body mass index (BMI) (aOR = 1.052, 95% CI = 1.044-1.061), hypertension (aOR = 2.017, 95% CI = 1.763-2.306), diabetes (aOR = 2.673, 95% CI = 2.119-3.370), vigorous recreational activities (aOR = 0.6369, 95% CI = 0.5725-0.7085), moderate recreational activity (aOR = 0.7681, 95% CI = 0.6935-0.8574) and cadmium (aOR = 1.295, 95% CI = 1.168-1.436) were closely related to hepatitis B virus (HBV) susceptibility. After adjusting for these confounding factors, multivariate logistic regression analysis showed that the odds ratio of HBV susceptibility was positively correlated with the level of cadmium in serum. The effectiveness of the model was then evaluated by establishing a nomogram, and by calibration curves, ROC curves, and clinical decision curves. Our study shows that cadmium exposure is positively associated with HBV susceptibility risk in the US population, and the constructed model has clinical significance.
Topics: Humans; Child; Nutrition Surveys; Cadmium; Cross-Sectional Studies; Hepatitis B; Hepatitis B virus; Risk Factors
PubMed: 37558919
DOI: 10.1007/s11356-023-29267-1 -
The Journal of Biological Chemistry Sep 2023Hepatitis B virus (HBV) is a hepatotropic DNA virus that has a very compact genome. Due to this genomic density, several distinct mechanisms are used to facilitate the...
Hepatitis B virus (HBV) is a hepatotropic DNA virus that has a very compact genome. Due to this genomic density, several distinct mechanisms are used to facilitate the viral life cycle. Recently, accumulating evidence show that G-quadruplex (G4) in different viruses play essential regulatory roles in key steps of the viral life cycle. Although G4 structures in the HBV genome have been reported, their function in HBV replication remains elusive. In this study, we treated an HBV replication-competent cell line and HBV-infected cells with the G4 structure stabilizer pyridostatin (PDS) and evaluated different HBV replication markers to better understand the role played by the G4. In both models, we found PDS had no effect on viral precore RNA (pcRNA) or pre-genomic RNA (pgRNA), but treatment did increase HBeAg/HBc ELISA reads and intracellular levels of viral core/capsid protein (HBc) in a dose-dependent manner, suggesting post-transcriptional regulation. To further dissect the mechanism of G4 involvement, we used in vitro-synthesized HBV pcRNA and pgRNA. Interestingly, we found PDS treatment only enhanced HBc expression from pgRNA but not HBeAg expression from pcRNA. Our bioinformatic analysis and CD spectroscopy revealed that pgRNA harbors a conserved G4 structure. Finally, we introduced point mutations in pgRNA to disrupt its G4 structure and observed the resulting mutant failed to respond to PDS treatment and decreased HBc level in in vitro translation assay. Taken together, our data demonstrate that HBV pgRNA contains a G4 structure that plays a vital role in the regulation of viral mRNA translation.
Topics: Humans; Capsid Proteins; Hepatitis B; Hepatitis B e Antigens; Hepatitis B virus; RNA, Viral; Viral Core Proteins; Virus Replication; Cell Line; G-Quadruplexes; Protein Biosynthesis; Mutation; Aminoquinolines
PubMed: 37567479
DOI: 10.1016/j.jbc.2023.105151 -
Virology Aug 2023Hepatitis B virus (HBV) infects the liver and is a major risk factor for liver cirrhosis and hepatocellular carcinoma. Approaches for an effective cure are thwarted by...
Hepatitis B virus (HBV) infects the liver and is a major risk factor for liver cirrhosis and hepatocellular carcinoma. Approaches for an effective cure are thwarted by limited knowledge of virus-host interactions. Herein, we identified SCAP as a novel host factor that regulates HBV gene expression. SCAP, sterol regulatory element-binding protein (SREBP) cleavage-activating protein, is an integral membrane protein located in the endoplasmic reticulum. The protein plays a central role in controlling lipid synthesis and uptake by cells. We found that gene silencing of SCAP significantly inhibited HBV replication; furthermore, knockdown of SREBP2 but not SREBP1, the downstream effectors of SCAP, reduced HBs antigen production from HBV infected primary hepatocytes. We also demonstrated that knockdown of SCAP resulted in activation of interferons (IFNs) and IFN stimulated genes (ISGs). Conversely, ectopic expression of SREBP2 in SCAP-deficient cells restored expression of IFNs and ISGs. Importantly, expression of SREBP2 restored HBV production in SCAP knockdown cells, suggesting that SCAP participates in HBV replication through an effect on IFN production via its downstream effector SREBP2. This observation was further confirmed by blocking IFN signaling by an anti-IFN antibody, which restored HBV infection in SCAP-deficient cells. This led to the conclusion that SCAP regulates the IFN pathway through SREBP, thereby affecting the HBV lifecycle. This is the first study to reveal the involvement of SCAP in regulation of HBV infection. These results may facilitate development of new antiviral strategies against HBV.
Topics: Humans; Hepatitis B; Hepatitis B virus; Interferons; Liver Neoplasms; Signal Transduction; Sterol Regulatory Element Binding Protein 1
PubMed: 37437369
DOI: 10.1016/j.virol.2023.07.001 -
Journal of Virology Oct 2023Chronic hepatitis B is the most important cause of liver cancer worldwide and affects more than 290 million people. Current treatments are mostly suppressive and rarely...
Chronic hepatitis B is the most important cause of liver cancer worldwide and affects more than 290 million people. Current treatments are mostly suppressive and rarely lead to a cure. Therefore, there is a need for novel and curative drugs that target the host or the causative agent, hepatitis B virus itself. Capsid assembly modulators are an interesting class of antiviral molecules that may one day become part of curative treatment regimens for chronic hepatitis B. Here we explore the characteristics of a particularly interesting subclass of capsid assembly modulators. These so-called non-HAP CAM-As have intriguing properties in cell culture but also clear virus-infected cells from the mouse liver in a gradual and sustained way. We believe they represent a considerable improvement over previously reported molecules and may one day be part of curative treatment combinations for chronic hepatitis B.
Topics: Animals; Humans; Mice; Antiviral Agents; Capsid; Capsid Proteins; Cells, Cultured; Hepatitis B virus; Hepatitis B, Chronic; In Vitro Techniques; Virus Assembly; Disease Models, Animal
PubMed: 37754761
DOI: 10.1128/jvi.00722-23 -
Immunology Apr 2024Hepatocellular carcinoma (HCC) is a major contributor to cancer-related deaths worldwide. Hepatitis B virus (HBV) infection is a major etiologic factor leading to HCC.... (Review)
Review
Hepatocellular carcinoma (HCC) is a major contributor to cancer-related deaths worldwide. Hepatitis B virus (HBV) infection is a major etiologic factor leading to HCC. While there have been significant advancements in controlling HBV replication, achieving a complete cure for HBV-related HCC (HBV-HCC) remains an intricate challenge. HBV persistence is attributed to a myriad of mechanisms, encompassing both innate and adaptive immune responses. Regulatory T cells (Tregs) are pivotal in upholding immune tolerance and modulating excessive immune activation. During HBV infection, Tregs mediate specific T cell suppression, thereby contributing to both persistent infection and the mitigation of liver inflammatory responses. Studies have demonstrated an augmented expression of circulating and intrahepatic Tregs in HBV-HCC, which correlates with impaired CD8 T cell function. Consequently, Tregs play a dual role in the context of HBV infection and the progression of HBV-HCC. In this comprehensive review, we discuss pertinent studies concerning Tregs in HBV infection, HBV-related cirrhosis and HCC. Furthermore, we summarize Treg responses to antiviral therapy and provide Treg-targeted therapies specific to HBV and HCC.
Topics: Humans; Hepatitis B virus; Carcinoma, Hepatocellular; T-Lymphocytes, Regulatory; Hepatitis B, Chronic; Liver Neoplasms; Hepatitis B
PubMed: 38093705
DOI: 10.1111/imm.13738