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Cell Death & Disease Jan 2024Eukaryotic five-methylcytosine (mC) is an important regulator of viral RNA splicing, stability, and translation. However, its role in HBV replication remains largely...
Eukaryotic five-methylcytosine (mC) is an important regulator of viral RNA splicing, stability, and translation. However, its role in HBV replication remains largely unknown. In this study, functional mC sites are identified in hepatitis B virus (HBV) mRNA. The mC modification at nt 1291 is not only indispensable for Aly/REF export factor (ALYREF) recognition to promote viral mRNA export and HBx translation but also for the inhibition of RIG-I binding to suppress interferon-β (IFN-β) production. Moreover, NOP2/Sun RNA methyltransferase 2 (NSUN2) catalyzes the addition of mC to HBV mRNA and is transcriptionally downregulated by the viral protein HBx, which suppresses the binding of EGR1 to the NSUN2 promoter. Additionally, NSUN2 expression correlates with mC modification of type I IFN mRNA in host cells, thus, positively regulating IFN expression. Hence, the delicate regulation of NSUN2 expression induces mC modification of HBV mRNA while decreasing the levels of mC in host IFN mRNA, making it a vital component of the HBV life cycle. These findings provide new molecular insights into the mechanism of HBV-mediated IFN inhibition and may inform the development of new IFN-α based therapies.
Topics: Hepatitis B virus; Virus Replication; Antiviral Agents; RNA, Messenger; Epigenesis, Genetic
PubMed: 38216565
DOI: 10.1038/s41419-023-06412-9 -
Chinese Journal of Natural Medicines Nov 2023Chronic hepatitis B (CHB) infections caused by the hepatitis B virus (HBV) continue to pose a significant global public health challenge. Currently, the approved... (Review)
Review
Chronic hepatitis B (CHB) infections caused by the hepatitis B virus (HBV) continue to pose a significant global public health challenge. Currently, the approved treatments for CHB are limited to interferon and nucleos(t)ide analogs, both of which have their limitations, and achieving a complete cure remains an elusive goal. Therefore, the identification of new therapeutic targets and the development of novel antiviral strategies are of utmost importance. Natural products (NPs) constitute a class of substances known for their diverse chemical structures, wide-ranging biological activities, and low toxicity profiles. They have shown promise as potential candidates for combating various diseases, with a substantial number demonstrating anti-HBV properties. This comprehensive review focuses on the current applications of NPs in the fight against HBV and provides a summary of their antiviral mechanisms, considering their impact on the viral life cycle and host hepatocytes. By offering insights into the world of anti-HBV NPs, this review aims to furnish valuable information to support the future development of antiviral drugs.
Topics: Humans; Hepatitis B virus; Hepatitis B, Chronic; Antiviral Agents; Biological Products; Hepatocytes
PubMed: 38035936
DOI: 10.1016/S1875-5364(23)60505-9 -
BMC Health Services Research Aug 2023Achieving World Health Organization (WHO) targets for viral hepatitis elimination will require simplification and decentralisation of care, supported through... (Review)
Review
Training the healthcare workforce to support task-shifting and viral hepatitis elimination: a global review of English language online trainings and in-person workshops for management of hepatitis B and C infection.
BACKGROUND
Achieving World Health Organization (WHO) targets for viral hepatitis elimination will require simplification and decentralisation of care, supported through task-shifting and training of non-specialist frontline healthcare workers. To inform development of national health worker trainings in viral hepatitis, we review and summarise available online and workshop trainings for management of hepatitis B virus (HBV) and hepatitis C virus (HCV).
METHODS
We performed a systematic search of PubMed, Embase, Web of Science, conference abstracts, and grey literature using Google to identify online and in-person workshop trainings for health workers focused on HBV and/or HCV. Additional trainings were identified through a WHO regional network. We included online trainings written in English and in-person workshops developed for low-and-middle-income countries (LMICs). Available curricula are summarised together with key operational features (e.g. training length, year developed/updated, developing institution) and programmatic features (e.g. content, mechanism for self-assessment, use of clinical case studies).
RESULTS
A total of 30 trainings met our inclusion criteria (10 online trainings; 20 in-person workshops). 50% covered both HBV and HCV, 13% HBV alone and 37% HCV alone. Among online trainings, only 2 (20%) were specifically developed or adapted for LMICs; 70% covered all aspects of hepatitis care, including prevention, assessment, and treatment; 9 (90%) included guidance on when to refer to specialists, and 6 (60%) included modules on management in specific populations (e.g., people who inject drugs [PWID], prisoners, and children). Online trainings used different formats including text-based modules, narrated slide-sets, and interactive web-based modules. Most workshops (95%) were targeted towards non-specialty providers, and 50% were an integral part of a national strategy for viral hepatitis elimination. Workshop length ranged from several hours to multiple sessions over the course of months, and many were part of a blended educational model, which included other opportunities for ongoing learning (e.g., telementorship).
CONCLUSION
This compendium of online and in-person workshop trainings for HBV and HCV is a useful resource for national hepatitis programmes developing training curricula for non-specialists. Additional online training curricula are needed for use in LMICs, and additional materials are needed to address management challenges in key populations, such as PWID.
Topics: Child; Humans; Substance Abuse, Intravenous; Hepatitis B; Hepatitis C; Hepatitis B virus; Hepacivirus; Health Personnel; Delivery of Health Care; Workforce
PubMed: 37568106
DOI: 10.1186/s12913-023-09777-x -
Journal of Viral Hepatitis Jul 2024The current World Health Organization (WHO) Hepatitis Elimination Strategy suffers from lack of a target for diagnosing or expunging occult HBV infection. A sizable... (Review)
Review
The current World Health Organization (WHO) Hepatitis Elimination Strategy suffers from lack of a target for diagnosing or expunging occult HBV infection. A sizable segment of the global population has an undetected HBV infection, particularly the high-risk populations and those residing in countries like India with intermediate endemicity. There is growing proof that people with hidden HBV infection can infect others, and that these infections are linked to serious chronic hepatic complications, especially hepatocellular carcinoma. Given the current diagnostic infrastructure in low-resource settings, the WHO 2030 objective of obliterating hepatitis B appears to be undeniably challenging to accomplish. Given the molecular basis of occult HBV infection strongly linked to intrahepatic persistence, patients may inexplicably harbour HBV genomes for a prolonged duration without displaying any pronounced clinical or biochemical signs of liver disease, and present histological signs of moderate degree necro-inflammation, diffuse fibrosis, and hence the international strategy to eradicate viral hepatitis warrants inclusion of occult HBV infection.
Topics: Humans; World Health Organization; Hepatitis B virus; Hepatitis B; Global Health; Disease Eradication
PubMed: 38578122
DOI: 10.1111/jvh.13928 -
Journal of Virology Jul 2023Hepatitis B virus (HBV) chronically infects approximately 300 million people worldwide, and permanently repressing transcription of covalently closed circular DNA...
Hepatitis B virus (HBV) chronically infects approximately 300 million people worldwide, and permanently repressing transcription of covalently closed circular DNA (cccDNA), the episomal viral DNA reservoir, is an attractive approach toward curing HBV. However, the mechanism underlying cccDNA transcription is only partially understood. In this study, by illuminating cccDNA of wild-type HBV (HBV-WT) and transcriptionally inactive HBV that bears a deficient HBV X gene (HBV-ΔX), we found that the HBV-ΔX cccDNA more frequently colocalizes with promyelocytic leukemia (PML) bodies than that of HBV-WT cccDNA. A small interfering RNA (siRNA) screen targeting 91 PML body-related proteins identified SMC5-SMC6 localization factor 2 (SLF2) as a host restriction factor of cccDNA transcription, and subsequent studies showed that SLF2 mediates HBV cccDNA entrapment in PML bodies by interacting with the SMC5/6 complex. We further showed that the region of SLF2 comprising residues 590 to 710 interacts with and recruits the SMC5/6 complex to PML bodies, and the C-terminal domain of SLF2 containing this region is necessary for repression of cccDNA transcription. Our findings shed new light on cellular mechanisms that inhibit HBV infection and lend further support for targeting the HBx pathway to repress HBV activity. Chronic HBV infection remains a major public health problem worldwide. Current antiviral treatments rarely cure the infection, as they cannot clear the viral reservoir, cccDNA, in the nucleus. Therefore, permanently silencing HBV cccDNA transcription represents a promising approach for a cure of HBV infection. Our study provides new insights into the cellular mechanisms that restrict HBV infection, revealing the role of SLF2 in directing HBV cccDNA to PML bodies for transcriptional repression. These findings have important implications for the development of antiviral therapies against HBV.
Topics: Humans; Hepatitis B virus; Hepatitis B; DNA, Circular; Antiviral Agents; DNA, Viral; Promyelocytic Leukemia Protein; Leukemia; Virus Replication; Chromosomal Proteins, Non-Histone; Cell Cycle Proteins
PubMed: 37338350
DOI: 10.1128/jvi.00328-23 -
Journal of Hepatology Sep 2023
Topics: Hepatitis B virus; Hepatitis B Core Antigens; DNA, Viral; Hepatitis B e Antigens
PubMed: 36965779
DOI: 10.1016/j.jhep.2023.03.008 -
Hepatology International Oct 2023Restoration of HBV-specific T cell immunity is a promising approach for the functional cure of chronic Hepatitis B (CHB), necessitating the development of valid assays...
BACKGROUND
Restoration of HBV-specific T cell immunity is a promising approach for the functional cure of chronic Hepatitis B (CHB), necessitating the development of valid assays to boost and monitor HBV-specific T cell responses in patients with CHB.
METHODS
We analyzed hepatitis B virus (HBV) core- and envelope (env)-specific T cell responses using in vitro expanded peripheral blood mononuclear cells (PBMCs) from patients with CHB exhibiting different immunological phases, including immune tolerance (IT), immune activation (IA), inactive carrier (IC), and HBeAg-negative hepatitis (ENEG). Additionally, we evaluated the effects of metabolic interventions, including mitochondria-targeted antioxidants (MTA), polyphenolic compounds, and ACAT inhibitors (iACAT), on HBV-specific T-cell functionality.
RESULTS
We found that HBV core- and env-specific T cell responses were finely coordinated and more profound in IC and ENEG than in the IT and IA stages. HBV env-specific T cells were more dysfunctional but prone to respond to metabolic interventions using MTA, iACAT, and polyphenolic compounds than HBV core-specific T-cells. The responsiveness of HBV env-specific T cells to metabolic interventions can be predicted by the eosinophil (EO) count and the coefficient of variation of red blood cell distribution width (RDW-CV).
CONCLUSION
These findings may provide valuable information for metabolically invigorating HBV-specific T-cells to treat CHB.
Topics: Humans; T-Lymphocytes; Hepatitis B virus; Hepatitis B, Chronic; Leukocytes, Mononuclear; Hepatitis B e Antigens; Hepatitis B Surface Antigens
PubMed: 36976426
DOI: 10.1007/s12072-023-10490-4 -
Viruses Oct 2023Chronic hepatitis B affects >300 million people worldwide and is a major cause of liver disease, causing ~800,000 deaths each year [...].
Chronic hepatitis B affects >300 million people worldwide and is a major cause of liver disease, causing ~800,000 deaths each year [...].
Topics: Humans; Hepatitis B virus; Hepatitis B, Chronic; Hepatitis B
PubMed: 38005851
DOI: 10.3390/v15112173 -
BMC Medicine Aug 2023
Topics: Pregnancy; Female; Humans; Infant, Newborn; Mothers; Hepatitis B virus; Pregnancy Complications, Infectious; Hepatitis
PubMed: 37533026
DOI: 10.1186/s12916-023-03006-2 -
Scientific Reports Aug 2023Chronic hepatitis B virus (HBV) infection is a major medical concern worldwide. Current treatments for HBV infection effectively inhibit virus replication; however,...
Chronic hepatitis B virus (HBV) infection is a major medical concern worldwide. Current treatments for HBV infection effectively inhibit virus replication; however, these treatments cannot cure HBV and novel treatment-strategies should be necessary. In this study, we identified tripartite motif-containing protein 26 (TRIM26) could be a supportive factor for HBV replication. Small interfering RNA-mediated TRIM26 knockdown (KD) modestly attenuated HBV replication in human hepatocytes. Endogenous TRIM26 physically interacted with HBV core protein (HBc), but not polymerase and HBx, through the TRIM26 SPRY domain. Unexpectedly, TRIM26 inhibited HBc ubiquitination even though TRIM26 is an E3 ligase. HBc was degraded by TRIM26 KD in Huh-7 cells, whereas the reduction was restored by a proteasome inhibitor. RING domain-deleted TRIM26 mutant (TRIM26ΔR), a dominant negative form of TRIM26, sequestered TRIM26 from HBc, resulting in promoting HBc degradation. Taking together, this study demonstrated that HBV utilizes TRIM26 to avoid the proteasome-dependent HBc degradation. The interaction between TRIM26 and HBc might be a novel therapeutic target against HBV infection.
Topics: Humans; Hepatitis B virus; Hepatitis B, Chronic; Proteasome Endopeptidase Complex; Hepatitis B; Viral Core Proteins; Tripartite Motif Proteins; Ubiquitin-Protein Ligases
PubMed: 37604854
DOI: 10.1038/s41598-023-40688-3