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Viruses May 2024The hepatitis B virus (HBV) infects hepatocytes and hijacks host cellular mechanisms for its replication. Host proteins can be frontline effectors of the cell's defense... (Review)
Review
The hepatitis B virus (HBV) infects hepatocytes and hijacks host cellular mechanisms for its replication. Host proteins can be frontline effectors of the cell's defense and restrict viral replication by impeding multiple steps during its intracellular lifecycle. This review summarizes many of the well-described restriction factors, their mechanisms of restriction, and counteractive measures of HBV, with a special focus on viral transcription. We discuss some of the limitations and knowledge gaps about the restriction factors, highlighting how these factors may be harnessed to facilitate therapeutic strategies against HBV.
Topics: Hepatitis B virus; Virus Replication; Humans; Host-Pathogen Interactions; Hepatitis B; Hepatocytes; Animals
PubMed: 38793645
DOI: 10.3390/v16050764 -
Gut Mar 2024Chronic hepatitis B (CHB) caused by HBV infection greatly increases the risk of liver cirrhosis and hepatocellular carcinoma. Hepatitis B surface antigen (HBsAg) plays...
OBJECTIVES
Chronic hepatitis B (CHB) caused by HBV infection greatly increases the risk of liver cirrhosis and hepatocellular carcinoma. Hepatitis B surface antigen (HBsAg) plays critical roles in the pathogenesis of CHB. HBsAg loss is the key indicator for cure of CHB, but is rarely achieved by current approved anti-HBV drugs. Therefore, novel anti-HBV strategies are urgently needed to achieve sustained HBsAg loss.
DESIGN
We developed multiple chimeric antigen receptors (CARs) based on single-chain variable fragments (scFvs, namely MA18/7-scFv and G12-scFv), respectively, targeting HBV large and small envelope proteins. Their impacts on HBsAg secretion and HBV infection, and the underlying mechanisms, were extensively investigated using various cell culture models and HBV mouse models.
RESULTS
After secretory signal peptide mediated translocation into endoplasmic reticulum (ER) and secretory pathway, MA18/7-scFv and CARs blocked HBV infection and virion secretion. G12-scFv preferentially inhibited virion secretion, while both its CAR formats and crystallisable fragment (Fc)-attached versions blocked HBsAg secretion. G12-scFv and G12-CAR arrested HBV envelope proteins mainly in ER and potently inhibited HBV budding. Furthermore, G12-scFv-Fc and G12-CAR-Fc strongly suppressed serum HBsAg up to 130-fold in HBV mouse models. The inhibitory effect lasted for at least 8 weeks when delivered by an adeno-associated virus vector.
CONCLUSION
CARs possess direct antiviral activity, besides the well-known application in T-cell therapy. Fc attached G12-scFv and G12-CARs could provide a novel approach for reducing circulating HBsAg.
Topics: Mice; Animals; Hepatitis B Surface Antigens; Hepatitis B virus; Receptors, Chimeric Antigen; Endoplasmic Reticulum; Liver Neoplasms; Hepatitis B, Chronic; Hepatitis B
PubMed: 37973365
DOI: 10.1136/gutjnl-2023-330537 -
Emerging Microbes & Infections Dec 2023Chronic hepatitis B virus (HBV) infection remains one of the major global public health concerns, and it develop into liver fibrosis, cirrhosis, and hepatocellular...
Chronic hepatitis B virus (HBV) infection remains one of the major global public health concerns, and it develop into liver fibrosis, cirrhosis, and hepatocellular carcinoma. Recent evidence suggests that endosomal and autophagic vesicles are beneficial for HBV replication. However, it has not been well elucidated how HBV exploits such intracellular vesicle systems for its replication. RAB5A, a member of small GTPase family, plays crucial roles in early endosome biogenesis and autophagy initiation. We observed that RAB5A mRNA and protein levels were significantly increased in HBV-expressing hepatoma cell lines as well as in liver tissue samples from chronic HBV-infected patients. Moreover, RAB5A silencing inhibited HBV replication and subviral particle (SVP) expression significantly in HBV-transfected and -infected hepatoma cells, whereas RAB5A overexpression increased them. Mechanistically, RAB5A increases HBV replication through enhancement of early endosome (EE) - late endosome (LE) activation by interacting with EEA1, as well as enhancing autophagy induction by interacting with VPS34. Additionally, HBV infection enhances RAB5A-mediated dual activation of EE-LE system and autophagy. Collectively, our findings highlight that HBV utilizes RAB5A-mediated dual activation of endosomal and autophagic vesicle pathways for its own replication and persistence. Therefore, RAB5A is a potential target for chronic HBV infection treatment.
Topics: Humans; Autophagy; Carcinoma, Hepatocellular; Endosomes; Hepatitis B; Hepatitis B virus; Hepatitis B, Chronic; Monomeric GTP-Binding Proteins; Virus Replication
PubMed: 37725090
DOI: 10.1080/22221751.2023.2261556 -
Frontiers in Immunology 2023Immune cells play crucial roles in the development of chronic hepatitis B virus (HBV) infection, leading to cirrhosis and hepatocellular carcinoma (HCC). However, their...
INTRODUCTION
Immune cells play crucial roles in the development of chronic hepatitis B virus (HBV) infection, leading to cirrhosis and hepatocellular carcinoma (HCC). However, their functions at different disease stages are not fully understood.
METHODS
In this study, we used single-cell RNA sequencing (scRNA-seq) to characterize the human liver immune microenvironment at different disease stages. We analyzed scRNA-seq data from 118,455 immune cells obtained from livers of six healthy individuals, four patients with HBV infection, five patients with HBV cirrhosis, and three patients with HBV-associated HCC.
RESULTS
Our results showed an accumulation of scar-associated macrophages during disease progression, and we identified two relevant immune subsets, Macrophage-CD9/IL18 and macrophage-CD9/IFI6. Macrophage-CD9/IL18 expanded from HBV infection to cirrhosis, while macrophage-CD9/IFI6 expanded from cirrhosis to HCC. We verified the existence of Macrophage-CD9/IFI6 using multiplex immunofluorescence staining. We also found an increase in cytotoxic NK Cell-GNLY during progression from cirrhosis to HCC. Additionally, the proportion of CD4 T cell-TNFAIP3, CD8 T cell-TNF (effector CD8 T cells), and CD8 T cell-CD53 increased, while the proportion of Treg cells decreased from HBV infection to cirrhosis. The proportion of Treg and CD8 T cell-LAG3 (Exhausted CD8 T cell) enhanced, while the proportion of CD8 T cell-TNF (effector CD8 T cells) decreased from cirrhosis to HCC. Furthermore, GSEA enrichment analyses revealed that MAPK, ERBB, and P53 signaling pathways in myeloid cells were gradually inhibited from HBV infection to cirrhosis and HCC.
DISCUSSION
Our study provides important insights into changes in the hepatic immune environment during the progression of HBV-related liver disease, which may help improve the management of HBV-infected liver diseases.
Topics: Humans; Carcinoma, Hepatocellular; Hepatitis B virus; Hepatitis B, Chronic; Liver Neoplasms; Interleukin-18; Hepatitis B; Liver Cirrhosis; Tumor Microenvironment
PubMed: 38116005
DOI: 10.3389/fimmu.2023.1320414 -
International Journal of Infectious... Sep 2023
Topics: Humans; Hepatitis B virus; Mental Disorders
PubMed: 37507084
DOI: 10.1016/j.ijid.2023.07.028 -
Journal of Hepatology Feb 2024Chronic co-infection with HBV and HDV leads to the most aggressive form of chronic viral hepatitis. To date, no treatment induces efficient viral clearance, and a better...
BACKGROUND & AIMS
Chronic co-infection with HBV and HDV leads to the most aggressive form of chronic viral hepatitis. To date, no treatment induces efficient viral clearance, and a better characterization of virus-host interactions is required to develop new therapeutic strategies.
METHODS
Using loss-of-function strategies, we validated the unexpected proviral activity of Janus kinase 1 (JAK1) - a key player in innate immunity - in the HDV life cycle and determined its mechanism of action on HDV through various functional analyses including co-immunoprecipitation assays.
RESULTS
We confirmed the key role of JAK1 kinase activity in HDV infection. Moreover, our results suggest that JAK1 inhibition is associated with a modulation of ERK1/2 activation and S-HDAg phosphorylation, which is crucial for viral replication. Finally, we showed that FDA-approved JAK1-specific inhibitors are efficient antivirals in relevant in vitro models including primary human hepatocytes.
CONCLUSIONS
Taken together, we uncovered JAK1 as a key host factor for HDV replication and a potential target for new antiviral treatment.
IMPACT AND IMPLICATIONS
Chronic hepatitis D is the most aggressive form of chronic viral hepatitis. As no curative treatment is currently available, new therapeutic strategies based on host-targeting agents are urgently needed. Here, using loss-of-function strategies, we uncover an unexpected interaction between JAK1, a major player in the innate antiviral response, and HDV infection. We demonstrated that JAK1 kinase activity is crucial for both the phosphorylation of the delta antigen and the replication of the virus. By demonstrating the antiviral potential of several FDA-approved JAK1 inhibitors, our results could pave the way for the development of innovative therapeutic strategies to tackle this global health threat.
Topics: Humans; Hepatitis Delta Virus; Janus Kinase 1; Hepatitis B virus; Hepatitis D, Chronic; Antiviral Agents; Virus Replication
PubMed: 37925078
DOI: 10.1016/j.jhep.2023.10.030 -
Inflammation Oct 2023Acute liver failure (ALF) is a rare and complicated disease with a high mortality rate. Emergency liver transplantation is the only treatment method that can improve the...
Acute liver failure (ALF) is a rare and complicated disease with a high mortality rate. Emergency liver transplantation is the only treatment method that can improve the ALF prognosis. However, its clinical application remains limited owing to the aggressive nature of liver transplantation, limited donors, and high postoperative mortality. The study investigated the effect of m6A on the immune microenvironment of hepatitis B virus-related ALF (HBV-ALF). In this study, the gene expression data of 47 normal people and 42 HBV-ALF patients were downloaded from the Gene Expression Omnibu (GEO) database. The known 23 m6A regulators which mediated RNA modification patterns were compared and analyzed in these two groups, and the gene diagnosis model of HBV-ALF patients was established based on the analysis results. In addition, we used unsupervised clustering to identify different m6A RNA methylation modification patterns in HBV-ALF based on m6A regulators, and evaluated the immune infiltration and biological differences in these subtypes. In addition, the relationship between m6A genes and immune cell activation in HBV-ACLF patients was explored by immune infiltration analysis. Nineteen m6A regulators mediated RNA methylation (m6A regulators for short) were differentially expressed in HBV-ALF and control groups. m6A regulators could well distinguish control samples from HBV-ALF samples, and m6A regulators might be used as a basis for diagnosing HBV-ALF patients. Immune cells such as activated CD8 T cells, activated B cells, and activated CD4 T cells might play important roles in HBV-ALF, and m6A regulators were closely associated with immune cell infiltration. ALKBH15, CBLL1, IGF2BP2, IGF2BP3, and ZC3H13 were significantly associated with immune cells. Considering 23 m6A regulators, HBV-ALF patients could be classified into two subtypes (cluster 1 and cluster 2) based on different immune cell infiltration. m6A regulators of the IGFBP and YHDF families have extremely different levels in these two subtypes. Differential immune cell infiltration among these subtypes was observed, a total of 913 differentially expressed genes among different m6A modification patterns was identified, and their biological functions were explored. m6A modification might play a crucial role in the diverse and complex immune microenvironment of HBV-ALF patients.
Topics: Humans; Hepatitis B virus; Methylation; RNA; Antigen-Antibody Complex; B-Lymphocytes; Ubiquitin-Protein Ligases; RNA-Binding Proteins
PubMed: 37256461
DOI: 10.1007/s10753-023-01841-2 -
Pathology, Research and Practice Sep 2023microRNAs (miRNAs) are small, non-coding RNA molecules that play crucial regulatory roles in numerous cellular processes. Recent investigations have highlighted the... (Review)
Review
microRNAs (miRNAs) are small, non-coding RNA molecules that play crucial regulatory roles in numerous cellular processes. Recent investigations have highlighted the significant involvement of miRNA-122 (miR-122) in the pathogenesis of infectious diseases caused by diverse pathogens, encompassing viral, bacterial, and parasitic infections. In the context of viral infections, miR-122 exerts regulatory control over viral replication by binding to the viral genome and modulating the host's antiviral response. For instance, in hepatitis B virus (HBV) infection, miR-122 restricts viral replication, while HBV, in turn, suppresses miR-122 expression. Conversely, miR-122 interacts with the hepatitis C virus (HCV) genome, facilitating viral replication. Regarding bacterial infections, miR-122 has been found to regulate host immune responses by influencing inflammatory cytokine production and phagocytosis. In Vibrio anguillarum infections, there is a significant reduction in miR-122 expression, contributing to the pathophysiology of bacterial infections. Toll-like receptor 14 (TLR14) has been identified as a novel target gene of miR-122, affecting inflammatory and immune responses. In the context of parasitic infections, miR-122 plays a crucial role in regulating host lipid metabolism and immune responses. For example, during Leishmania infection, miR-122-containing extracellular vesicles from liver cells are unable to enter infected macrophages, leading to a suppression of the inflammatory response. Furthermore, miR-122 exhibits promise as a potential biomarker for various infectious diseases. Its expression level in body fluids, particularly in serum and plasma, correlates with disease severity and treatment response in patients affected by HCV, HBV, and tuberculosis. This paper also discusses the potential of miR-122 as a biomarker in infectious diseases. In summary, this review provides a comprehensive and insightful overview of the emerging role of miR-122 in infectious diseases, detailing its mechanism of action and potential implications for the development of novel therapeutic strategies.
Topics: Humans; MicroRNAs; Hepatitis C; Hepatitis B; Hepatitis B virus; Hepacivirus; Biomarkers
PubMed: 37544130
DOI: 10.1016/j.prp.2023.154725 -
Scientific Reports Oct 2023The selection pressure imposed by the host immune system impacts hepatitis B virus (HBV) quasispecies variability. This study evaluates HBV genetic diversity in...
The selection pressure imposed by the host immune system impacts hepatitis B virus (HBV) quasispecies variability. This study evaluates HBV genetic diversity in different biological fluids. Twenty paired serum, oral fluid, and DBS samples from chronic HBV carriers were analyzed using both Sanger and next generation sequencing (NGS). The mean HBV viral load in serum was 5.19 ± 4.3 log IU/mL (median 5.29, IQR 3.01-7.93). Genotype distribution was: HBV/A1 55% (11/20), A2 15% (3/20), D3 10% (2/20), F2 15% (3/20), and F4 5% (1/20). Genotype agreement between serum and oral fluid was 100% (genetic distances 0.0-0.006), while that between serum and DBS was 80% (genetic distances 0.0-0.115). Two individuals presented discordant genotypes in serum and DBS. Minor population analysis revealed a mixed population. All samples displayed mutations in polymerase and/or surface genes. Major population analysis of the polymerase pointed to positions H122 and M129 as the most polymorphic (≥ 75% variability), followed by V163 (55%) and I253 (50%). Neither Sanger nor NGS detected any antiviral primary resistance mutations in the major populations. Minor population analysis, however, demonstrated the rtM204I resistance mutation in all individuals, ranging from 2.8 to 7.5% in serum, 2.5 to 6.3% in oral fluid, and 3.6 to 7.2% in DBS. This study demonstrated that different fluids can be used to assess HBV diversity, nonetheless, genotypic differences according to biological compartments can be observed.
Topics: Humans; Hepatitis B virus; Quasispecies; Hepatitis B, Chronic; Mutation; Genotype; DNA, Viral; Hepatitis B
PubMed: 37813888
DOI: 10.1038/s41598-023-43655-0 -
BMC Surgery Aug 2023Preoperative prediction of microvascular invasion (MVI) using a noninvasive method remain unresolved, especially in HBV-related in intrahepatic cholangiocarcinoma (ICC).... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND AIMS
Preoperative prediction of microvascular invasion (MVI) using a noninvasive method remain unresolved, especially in HBV-related in intrahepatic cholangiocarcinoma (ICC). This study aimed to build and validate a preoperative prediction model for MVI in HBV-related ICC.
METHODS
Patients with HBV-associated ICC undergoing curative surgical resection were identified. Univariate and multivariate logistic regression analyses were performed to determine the independent risk factors of MVI in the training cohort. Then, a prediction model was built by enrolling the independent risk factors. The predictive performance was validated by receiver operator characteristic curve (ROC) and calibration in the validation cohort.
RESULTS
Consecutive 626 patients were identified and randomly divided into the training (418, 67%) and validation (208, 33%) cohorts. Multivariate analysis showed that TBIL, CA19-9, tumor size, tumor number, and preoperative image lymph node metastasis were independently associated with MVI. Then, a model was built by enrolling former fiver risk factors. In the validation cohort, the performance of this model showed good calibration. The area under the curve was 0.874 (95% CI: 0.765-0.894) and 0.729 (95%CI: 0.706-0.751) in the training and validation cohort, respectively. Decision curve analysis showed an obvious net benefit from the model.
CONCLUSION
Based on clinical data, an easy model was built for the preoperative prediction of MVI, which can assist clinicians in surgical decision-making and adjuvant therapy.
Topics: Humans; Hepatitis B virus; Cholangiocarcinoma; CA-19-9 Antigen; Bile Duct Neoplasms; Bile Ducts, Intrahepatic
PubMed: 37592274
DOI: 10.1186/s12893-023-02139-8