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Journal of Virology Jun 2024The antiviral role of the tripartite motif-containing (TRIM) protein family , a member of the E3-ubiquitin ligase family, has recently been actively studied. Hepatitis B...
The antiviral role of the tripartite motif-containing (TRIM) protein family , a member of the E3-ubiquitin ligase family, has recently been actively studied. Hepatitis B virus (HBV) infection is a major contributor to liver diseases; however, the host factors regulated by cytokine-inducible TRIM21 to suppress HBV remain unclear. In this study, we showed the antiviral efficacy of TRIM21 against HBV in hepatoma cell lines, primary human hepatocytes isolated from patient liver tissues, and mouse model. Using TRIM21 knock-out cells, we confirmed that the antiviral effects of interferon-gamma, which suppress HBV replication, are diminished when TRIM21 is deficient. Northern blot analysis confirmed a reduction of HBV RNA levels by TRIM21. Using Luciferase reporter assay, we also discovered that TRIM21 decreases the activity of HBV enhancers, which play a crucial role in covalently closed circular DNA transcription. The participation of the RING domain and PRY-SPRY domain in the anti-HBV effect of TRIM21 was demonstrated through experiments using deletion mutants. We identified a novel interaction between TRIM21 and hepatocyte nuclear factor 4α (HNF4α) through co-immunoprecipitation assay. More specifically, ubiquitination assay revealed that TRIM21 promotes ubiquitin-mediated proteasomal degradation of HNF4α. HNF1α transcription is down-regulated as a result of the degradation of HNF4α, an activator for the HNF1α promoter. Therefore, the reduction of key HBV enhancer activators, HNF4α and HNF1α, by TRIM21 resulted in a decline in HBV transcription, ultimately leading to the inhibition of HBV replication.IMPORTANCEDespite extensive research efforts, a definitive cure for chronic hepatitis B remains elusive, emphasizing the persistent importance of this viral infection as a substantial public health concern. Although the risks associated with hepatitis B virus (HBV) infection are well known, host factors capable of suppressing HBV are largely uncharacterized. This study elucidates that tripartite motif-containing protein 21 (TRIM21) suppresses HBV transcription and consequently inhibits HBV replication by downregulating the hepatocyte nuclear factors, which are host factors associated with the HBV enhancers. Our findings demonstrate a novel anti-HBV mechanism of TRIM21 in interferon-gamma-induced anti-HBV activity. These findings may contribute to new strategies to block HBV.
Topics: Humans; Hepatitis B virus; Animals; Mice; Interferon-gamma; Hepatocytes; Virus Replication; Hepatocyte Nuclear Factor 4; Ribonucleoproteins; Hepatitis B; Hep G2 Cells; Cell Line, Tumor
PubMed: 38780244
DOI: 10.1128/jvi.00468-24 -
KLRG1-expressing CD8+ T cells are exhausted and polyfunctional in patients with chronic hepatitis B.PloS One 2024Killer cell lectin-like receptor G1 (KLRG1) has traditionally been regarded as an inhibitory receptor of T cell exhaustion in chronic infection and inflammation....
Killer cell lectin-like receptor G1 (KLRG1) has traditionally been regarded as an inhibitory receptor of T cell exhaustion in chronic infection and inflammation. However, its exact role in hepatitis B virus (HBV) infection remains elusive. CD8+ T cells from 190 patients with chronic hepatitis B were analyzed ex vivo for checkpoint and apoptosis markers, transcription factors, cytokines and subtypes in 190 patients with chronic hepatitis B. KLRG1+ and KLRG1- CD8+ T cells were sorted for transcriptome analysis. The impact of the KLRG1-E-cadherin pathway on the suppression of HBV replication mediated by virus-specific T cells was validated in vitro. As expected, HBV-specific CD8+ T cells expressed higher levels of KLRG1 and showed an exhausted molecular phenotype and function. However, despite being enriched for the inhibitory molecules, thymocyte selection-associated high mobility group box protein (TOX), eomesodermin (EOMES), and Helios, CD8+ T cells expressing KLRG1 produced significant levels of tumour necrosis factor (TNF)-α, interferon (IFN)-γ, perforin, and granzyme B, demonstrating not exhausted but active function. Consistent with the in vitro phenotypic assay results, RNA sequencing (RNA-seq) data showed that signature effector T cell and exhausted T cell genes were enriched in KLRG1+ CD8+ T cells. Furthermore, in vitro testing confirmed that KLRG1-E-cadherin binding inhibits the antiviral efficacy of HBV-specific CD8+ T cells. Based on these findings, we concluded that KLRG1+ CD8+ T cells are not only a terminally exhausted subgroup but also exhibit functional diversity, despite inhibitory signs in HBV infection.
Topics: Humans; CD8-Positive T-Lymphocytes; Lectins, C-Type; Receptors, Immunologic; Hepatitis B, Chronic; Female; Male; Hepatitis B virus; Adult; Middle Aged; Virus Replication; Cadherins; Perforin
PubMed: 38776335
DOI: 10.1371/journal.pone.0303945 -
Cell Communication and Signaling : CCS May 2024Hepatitis B Virus (HBV) is widely recognized as a "metabolic virus" that disrupts hepatic metabolic homeostasis, rendering it one of the foremost risk factors for...
INTRODUCTION
Hepatitis B Virus (HBV) is widely recognized as a "metabolic virus" that disrupts hepatic metabolic homeostasis, rendering it one of the foremost risk factors for hepatocellular carcinoma (HCC). Except for antiviral therapy, the fundamental principles underlying HBV and HBV HCC have remained unchanged, limiting HCC treatment options.
OBJECTIVES
In this study, we aim to identify the distinctive metabolic profile of HBV-associated HCC, with the promise of identifying novel metabolic targets that confer survival advantages and ultimately impede cancer progression.
METHODS
We employed a comprehensive methodology to evaluate metabolic alterations systematically. Initially, we analyzed transcriptomic and proteomic data obtained from a public database, subsequently validating these findings within our test cohort at both the proteomic and transcriptomic levels. Additionally, we conducted a comprehensive analysis of tissue metabolomics profiles, lipidomics, and the activity of the MAPK and AKT signaling pathway to corroborate the abovementioned changes.
RESULTS
Our multi-omics approach revealed distinct metabolic dysfunctions associated with HBV-associated HCC. Specifically, we observed upregulated steroid hormone biosynthesis, primary bile acid metabolism, and sphingolipid metabolism in HBV-associated HCC patients' serum. Notably, metabolites involved in primary bile acid and sphingolipids can activate the MAPK/mTOR pathway. Tissue metabolomics and lipidomics analyses further validated the serum metabolic alterations, particularly alterations in lipid composition and accumulation of unsaturated fatty acids.
CONCLUSION
Our findings emphasize the pivotal role of HBV in HCC metabolism, elucidating the activation of a unique MAPK/mTOR signaling axis by primary bile acids and sphingolipids. Moreover, the hyperactive MAPK/mTOR signaling axis transduction leads to significant reprogramming in lipid metabolism within HCC cells, further triggering the activation of the MAPK/mTOR pathway in turn, thereby establishing a self-feeding circle driven by primary bile acids and sphingolipids.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; TOR Serine-Threonine Kinases; Hepatitis B virus; Lipid Metabolism; Male; Lipids; Signal Transduction; MAP Kinase Signaling System; Hepatitis B; Middle Aged; Female
PubMed: 38773448
DOI: 10.1186/s12964-024-01619-5 -
Immunobiology May 2024Activation of the cGAS-STING pathway induces the production of type I interferons, initiating the antiviral immune response, which contributes to the clearance of...
BACKGROUND AND AIMS
Activation of the cGAS-STING pathway induces the production of type I interferons, initiating the antiviral immune response, which contributes to the clearance of pathogens. Previous studies have shown that STING agonists promote hepatitis B virus (HBV) clearance; however, few studies have investigated the effect of activating the cGAS-STING pathway in macrophages on HBV.
METHODS
The polarization status of HBV particle-stimulated RAW264.7 macrophages was analyzed. After stimulation with HBV particles, the analysis focused on determining whether the DNA sensors in RAW264.7 macrophages recognized the viral double-stranded DNA (dsDNA) and evaluating the activation of the cGAS-STING pathway. Coculture of mouse macrophages and hepatocytes harboring HBV was used to study the antiviral activity of HBV-stimulated RAW264.7 macrophages.
RESULTS
After stimulation with HBV particles, HBV relaxed circular DNA (rcDNA) was detected in RAW264.7 macrophages, and the protein expression of phospho-STING, phospho-TBK1, and phospho-IRF3 in the STING pathway was increased, as shown by Western blot analysis, which revealed that M1 polarization of macrophages was caused by increased expression of CD86. RT-PCR analyses revealed elevated expression of M1 macrophage polarization-associated cytokines such as TNFα, IL-1β, iNOS, and IFNα/β. In the coculture experiment, both HBsAg and HBeAg expression levels were significantly decreased in AML12-HBV1.3 cells cocultured with the supernatants of HBV-stimulated RAW264.7 macrophages.
CONCLUSION
The results suggest that macrophages can endocytose HBV particles. Additionally, viral dsDNA can be recognized by DNA pattern recognition receptors, which in turn activate the cGAS-STING pathway, promoting the M1 polarization of macrophages, while no significant M2 polarization is observed. Macrophages stimulated with HBV particles exhibit enhanced antiviral activity against HBV.
Topics: Hepatitis B virus; Animals; Nucleotidyltransferases; Mice; Macrophages; DNA, Viral; Membrane Proteins; RAW 264.7 Cells; Signal Transduction; Hepatitis B; Humans; Macrophage Activation; Hepatocytes; Interferon Regulatory Factor-3
PubMed: 38772101
DOI: 10.1016/j.imbio.2024.152810 -
Chinese Medical Journal Jun 2024Hepatitis B virus (HBV) infection is the primary cause of hepatocellular carcinoma (HCC) in China. The target population for HCC screening comprises individuals who test...
BACKGROUND
Hepatitis B virus (HBV) infection is the primary cause of hepatocellular carcinoma (HCC) in China. The target population for HCC screening comprises individuals who test positive for hepatitis B surface antigen (HBsAg). However, current data on the prevalence of HBV infection among individuals who are eligible for HCC screening in China are lacking. We aimed to assess the seroepidemiology of HBV infection among Chinese individuals eligible for HCC screening to provide the latest evidence for appropriate HCC screening strategies in China.
METHODS
Questionnaires including information of sex, age, ethnicity, marital status, educational level, source of drinking water, as well as smoking and alcohol consumption history and serum samples were collected from females aged 45-64 years and males aged 35-64 years in 21 counties from 4 provinces in eastern and central China between 2015 and 2023. Enzyme-linked immunosorbent assay methods were used to detect the serum HBV marker HBsAg.
RESULTS
A total of 603,082 individuals were enrolled, and serum samples were collected for analysis from January 1, 2015 to December 31, 2023. The prevalence of HBsAg positive in the study population was 5.23% (31,528/603,082). The prevalence of HBsAg positive was greater in males than in females (5.60% [17,660/315,183] vs . 4.82% [13,868/287,899], χ 2 = 187.52, P <0.0001). The elderly participants exhibited a greater prevalence of HBV infection than younger participants (χ 2 = 41.73, P <0.0001). Birth cohort analysis revealed an overall downward trend in HBV prevalence for both males and females. Individuals born in more recent cohorts exhibited a lower prevalence of HBV infection as compared to those born earlier.
CONCLUSIONS
The current prevalence of HBV infection remains above 5% in populations eligible for HCC screening in China. Further efforts should be made to increase the accessibility of HCC screening among individuals with HBV infection.
Topics: Humans; Male; Female; Middle Aged; China; Liver Neoplasms; Hepatitis B; Cross-Sectional Studies; Adult; Hepatitis B Surface Antigens; Hepatitis B virus; Prevalence; Carcinoma, Hepatocellular; Early Detection of Cancer; Surveys and Questionnaires; Seroepidemiologic Studies
PubMed: 38766992
DOI: 10.1097/CM9.0000000000003171 -
Frontiers in Cellular and Infection... 2024To analyze the amino acid substitution caused by mutations in the major hydrophilic region (MHR) of the S-region genes in the serum samples of occult hepatitis B virus...
OBJECTIVE
To analyze the amino acid substitution caused by mutations in the major hydrophilic region (MHR) of the S-region genes in the serum samples of occult hepatitis B virus infection (OBI), and to explore the reasons for the missed detection of HBsAg.
METHOD
The full-length gene of the S-region in hepatitis B virus(HBV) in the chronic hepatitis B virus(CHB)(10 samples) and OBI groups(42 samples) was amplified using a lab-developed, two-round PCR amplification technology. The PCR amplification products were sequenced/clone sequenced, and the nucleotide sequences of the S-region gene in HBV were compared to the respective genotype consensus sequence.
RESULTS
Only 20 of the 42 samples in the OBI group had the S-region genes successfully amplified, with the lowest HBV DNA load of 20.1IU/ml. As S-region genes in HBV, 68 cloned strains were sequenced. In the OBI and CHB groups MHR region, with a mutation rate of 3.21% (155/4828) and 0.70% (5/710). The genetic mutation rate was significantly higher in the OBI group than in the CHB group (P<0.05). The common mutation types in the MHR region were: I126T, L162R, K122E, C124R, and C147Y.Mutations at s122, s126, and s162 were associated with subgenotypes, most of which being C genotypes. The high-frequency mutation sites L162R and K122E found in this study have not been reported in previous literature.
CONCLUSION
The results of this study confirmed that MHR mutations can cause the missed detection of HBsAg, giving rise to OBI.
Topics: Humans; Hepatitis B Surface Antigens; Hepatitis B virus; Adult; Female; Male; Genotype; DNA, Viral; Middle Aged; Hepatitis B, Chronic; Mutation; Amino Acid Substitution; Viral Load; Sequence Analysis, DNA; Polymerase Chain Reaction; Hepatitis B; Mutation Rate; Aged; Young Adult
PubMed: 38766475
DOI: 10.3389/fcimb.2024.1368473 -
Scientific Reports May 2024Limited data exist on viral hepatitis among migrant populations. This study investigated the prevalence of current hepatitis B virus (HBV) infection and lifetime...
Limited data exist on viral hepatitis among migrant populations. This study investigated the prevalence of current hepatitis B virus (HBV) infection and lifetime hepatitis C virus (HCV) infection among Qatar's migrant craft and manual workers (CMWs), constituting 60% of the country's population. Sera collected during a nationwide COVID-19 population-based cross-sectional survey on CMWs between July 26 and September 9, 2020, underwent testing for HBsAg and HCV antibodies. Reactive samples underwent confirmatory testing, and logistic regression analyses were employed to explore associations with HBV and HCV infections. Among 2528 specimens tested for HBV infection, 15 were reactive, with 8 subsequently confirmed positive. Three samples lacked sufficient sera for confirmatory testing but were included in the analysis through multiple imputations. Prevalence of current HBV infection was 0.4% (95% CI 0.2-0.7%). Educational attainment and occupation were significantly associated with current HBV infection. For HCV infection, out of 2607 specimens tested, 46 were reactive, and 23 were subsequently confirmed positive. Prevalence of lifetime HCV infection was 0.8% (95% CI 0.5-1.2%). Egyptians exhibited the highest prevalence at 6.5% (95% CI 3.1-13.1%), followed by Pakistanis at 3.1% (95% CI 1.1-8.0%). Nationality, geographic location, and occupation were significantly associated with lifetime HCV infection. HBV infection is relatively low among CMWs, while HCV infection falls within the intermediate range, both compared to global and regional levels.
Topics: Humans; Qatar; Hepatitis B; Female; Transients and Migrants; Hepatitis C; Adult; Male; Prevalence; Cross-Sectional Studies; Middle Aged; Hepacivirus; Hepatitis B virus; Young Adult; COVID-19; Adolescent; Hepatitis B Surface Antigens; Hepatitis C Antibodies
PubMed: 38760415
DOI: 10.1038/s41598-024-61725-9 -
The Journal of International Medical... May 2024Recombinant human type II tumour necrosis factor receptor-antibody fusion protein (rh TNFR:Fc) is an immunosuppressant approved for treating rheumatoid arthritis (RA)....
Recombinant human type II tumour necrosis factor receptor-antibody fusion protein (rh TNFR:Fc) is an immunosuppressant approved for treating rheumatoid arthritis (RA). This case report describes a case of hepatitis B reactivation in a patient with drug-induced acute-on-chronic liver failure. A 58-year-old woman with a history of RA was treated with rh TNFR:Fc; and then subsequently received 25 mg rh TNFR:Fc, twice a week, as maintenance therapy. No anti-hepatitis B virus (HBV) preventive treatment was administered. Six months later, she was hospitalized with acute jaundice. HBV reactivation was observed, leading to acute-on-chronic liver failure. After active treatment, the patient's condition improved and she recovered well. Following careful diagnosis and treatment protocols are essential when treating RA with rh TNFR:Fc, especially in anti-hepatitis B core antigen antibody-positive patients, even when the HBV surface antigen and the HBV DNA are negative. In the case of HBV reactivation, liver function parameters, HBV surface antigen and HBV DNA should be closely monitored during treatment, and antiviral drugs should be used prophylactically when necessary, as fatal hepatitis B reactivation may occur in rare cases. A comprehensive evaluation and medication should be administered in a timely manner after evaluating the patient's physical condition and closely monitoring the patient.
Topics: Humans; Female; Middle Aged; Hepatitis B virus; Virus Activation; Recombinant Fusion Proteins; Hepatitis B; Arthritis, Rheumatoid; Liver Failure
PubMed: 38760056
DOI: 10.1177/03000605241252580 -
PloS One 2024Hepatitis B (HBV) and C virus (HCV) coinfection are the major causes of liver-related morbidity and mortality among people living with Human Immunodeficiency Virus...
BACKGROUND
Hepatitis B (HBV) and C virus (HCV) coinfection are the major causes of liver-related morbidity and mortality among people living with Human Immunodeficiency Virus (HIV). The burden of hepatitis among HIV-positive individuals has not been studied in the Afar region. Therefore, this study aimed to determine the prevalence of HBV and HCV coinfection and associated factors among HIV-positive patients in Afar Regional State, northeast Ethiopia.
METHODS
A cross-sectional study was conducted on 477 HIV-positive patients between February 2019 and May 2019. A structured and pretested questionnaire was used to collect socio-demographic data and associated factors. Five milliliters of blood was collected, and Hepatitis B surface antigen (HBsAg) and HCV antibodies were detected using rapid test kits. Positive samples were confirmed using enzyme-linked immunosorbent assay (ELISA). Binary and multivariable logistic regression analyses were performed to identify associated factors. Statistical significance was set at P <0.05.
RESULTS
Among the 477 study participants, 320/477(67.1%) of them were females and 157(32.9%) males. The overall prevalence of HIV-HBV and HIV-HCV coinfection was 25(5.2%) and 7(1.5%), respectively. Multi-sexual practice was significantly associated with HIV-HBV coinfection (AOR = 5.3; 95% CI: 1.2-24.4, P = 0.032).
CONCLUSION
The prevalence of both HIV-HBV and HIV-HCV coinfection was intermediate. Multi-sexual practice was significantly associated with HIV-HBV coinfection. Screening of all HIV-positive patients for HBV and HCV and health education regarding the transmission modes should be considered.
Topics: Humans; Ethiopia; Female; Male; Adult; Hepatitis B; Coinfection; Hepatitis C; HIV Infections; Cross-Sectional Studies; Middle Aged; Prevalence; Young Adult; Adolescent; Hepatitis B Surface Antigens; Hepacivirus; Risk Factors; Hepatitis B virus
PubMed: 38753600
DOI: 10.1371/journal.pone.0302453 -
Cancer Medicine May 2024Recent studies have found a high prevalence of hepatitis B virus (HBV) infection in patients with non-Hodgkin's lymphoma (NHL), especially B-cell non-Hodgkin's lymphoma...
OBJECTIVE
Recent studies have found a high prevalence of hepatitis B virus (HBV) infection in patients with non-Hodgkin's lymphoma (NHL), especially B-cell non-Hodgkin's lymphoma (B-NHL). However, most studies did not classify it and analyze the correlation between HBV and its various subtypes.
METHODS
The authors retrospectively analyzed 1424 patients with lymphoma. Differences in the prevalence of HBV infection in patients with different pathological types of lymphoma were analyzed. The clinical characteristics, progression-free survival (PFS), and overall survival (OS) of HBV-positive and negative B-NHL subtypes were compared according to HBV infection.
RESULTS
The HBV infection rate in NHL patients was 7.65%, which was higher than that in HL patients (2.59%, p < 0.05). The HBV infection rate in the B-NHL was higher than that in the T-cell non-Hodgkin's lymphoma (T-NHL) (8.14% vs. 4.95%). The HBV infection rate in the aggressive B-NHL was similar to that of the indolent B-NHL (8.30% vs. 7.88%), and the highest HBV infection rates were found in diffuse large B-cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma, but no significant differences in clinical characteristics, PFS, and OS were seen between HBV-positive and negative patients in the two subtypes.
CONCLUSIONS
There was an association between HBV infection and the development of NHL and HBV infection may play a role in the pathogenesis of B-NHL, but not T-NHL.
Topics: Humans; Retrospective Studies; Male; Female; Middle Aged; Hepatitis B; Adult; Aged; Hepatitis B virus; Young Adult; Prevalence; Lymphoma, Non-Hodgkin; Adolescent; Aged, 80 and over; Lymphoma, B-Cell; Progression-Free Survival
PubMed: 38752442
DOI: 10.1002/cam4.7284