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Experimental Cell Research Jul 2023Hepatitis B Virus (HBV) is the prevailing cause of chronic liver disease, which progresses to Hepatocellular carcinoma (HCC) in 75% of cases. It represents a serious... (Review)
Review
Hepatitis B Virus (HBV) is the prevailing cause of chronic liver disease, which progresses to Hepatocellular carcinoma (HCC) in 75% of cases. It represents a serious health concern being the fourth leading cause of cancer-related mortality worldwide. Treatments available to date fail to provide a complete cure with high chances of recurrence and related side effects. The lack of reliable, reproducible, and scalable in vitro modeling systems that could recapitulate the viral life cycle and represent virus-host interactions has hindered the development of effective treatments so far. The present review provides insights into the current in-vivo and in-vitro models used for studying HBV and their major limitations. We highlight the use of three-dimensional liver organoids as a novel and suitable platform for modeling HBV infection and HBV-mediated HCC. HBV organoids can be expanded, genetically altered, patient-derived, tested for drug discovery, and biobanked. This review also provides the general guidelines for culturing HBV organoids and highlights their several prospects for HBV drug discovery and screening.
Topics: Humans; Carcinoma, Hepatocellular; Hepatitis B virus; Liver Neoplasms; Organoids; Hepatitis B, Chronic
PubMed: 37142202
DOI: 10.1016/j.yexcr.2023.113618 -
The Journal of General Virology May 2024Since its discovery in 1965, our understanding of the hepatitis B virus (HBV) replication cycle and host immune responses has increased markedly. In contrast, our... (Review)
Review
Since its discovery in 1965, our understanding of the hepatitis B virus (HBV) replication cycle and host immune responses has increased markedly. In contrast, our knowledge of the molecular biology of hepatitis delta virus (HDV), which is associated with more severe liver disease, is less well understood. Despite the progress made, critical gaps remain in our knowledge of HBV and HDV replication and the mechanisms underlying viral persistence and evasion of host immunity. The International HBV Meeting is the leading annual scientific meeting for presenting the latest advances in HBV and HDV molecular virology, immunology, and epidemiology. In 2023, the annual scientific meeting was held in Kobe, Japan and this review summarises some of the advances presented at the Meeting and lists gaps in our knowledge that may facilitate the development of new therapies.
Topics: Hepatitis B virus; Humans; Virus Replication; Hepatitis Delta Virus; Hepatitis B; Molecular Biology; Japan; Hepatitis D; Host-Pathogen Interactions
PubMed: 38757942
DOI: 10.1099/jgv.0.001978 -
Cell Communication and Signaling : CCS Sep 2023Cholesterol plays a significant role in stabilizing lipid or membrane rafts, which are specific cellular membrane structures. Cholesterol is involved in numerous... (Review)
Review
Cholesterol plays a significant role in stabilizing lipid or membrane rafts, which are specific cellular membrane structures. Cholesterol is involved in numerous cellular processes, including regulating virus entry into the host cell. Multiple viruses have been shown to rely on cholesterol for virus entry and/or morphogenesis. Research indicates that reprogramming of the host's lipid metabolism is associated with hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in the progression to severe liver disease for viruses that cause chronic hepatitis. Moreover, knowing the precise mode of viral interaction with target cells sheds light on viral pathogenesis and aids in the development of vaccines and therapeutic targets. As a result, the area of cholesterol-lowering therapy is quickly evolving and has many novel antiviral targets and medications. It has been shown that microRNAs (miRNAs) either directly or indirectly target the viral genome, preventing viral replication. Moreover, miRNAs have recently been shown to be strong post-transcriptional regulators of the genes involved in lipid metabolism, particularly those involved in cholesterol homeostasis. As important regulators of lipid homeostasis in several viral infections, miRNAs have recently come to light. In addition, multiple studies demonstrated that during viral infection, miRNAs modulate several enzymes in the mevalonate/cholesterol pathway. As cholesterol metabolism is essential to the life cycle of viral hepatitis and other viruses, a sophisticated understanding of miRNA regulation may contribute to the development of a novel anti-HCV treatment. The mechanisms underlying the effectiveness of miRNAs as cholesterol regulators against viral hepatitis are explored in this review. Video Abstract.
Topics: Humans; Antibodies; Cell Membrane; Cholesterol; Hepatitis B virus; Hepatitis, Viral, Human
PubMed: 37710249
DOI: 10.1186/s12964-023-01250-w -
Viruses May 2024Hepatitis B and C viruses (HBV and HCV) are the leading causes of end-stage liver disease worldwide. Although there is a potent vaccine against HBV, many new infections... (Review)
Review
Hepatitis B and C viruses (HBV and HCV) are the leading causes of end-stage liver disease worldwide. Although there is a potent vaccine against HBV, many new infections are recorded annually, especially in poorly resourced places which have lax vaccination policies. Again, as HBV has no cure and chronic infection is lifelong, vaccines cannot help those already infected. Studies to thoroughly understand the HBV biology and pathogenesis are limited, leaving much yet to be understood about the genomic features and their role in establishing and maintaining infection. The current knowledge of the impact on disease progression and response to treatment, especially in hyperendemic regions, is inadequate. This calls for in-depth studies on viral biology, mainly for the purposes of coming up with better management strategies for infected people and more effective preventative measures for others. This information could also point us in the direction of a cure. Here, we discuss the progress made in understanding the genomic basis of viral activities leading to the complex interplay of the virus and the host, which determines the outcome of HBV infection as well as the impact of coinfections.
Topics: Humans; Hepatitis B virus; Hepatitis B; Coinfection; Genome, Viral; Animals
PubMed: 38793606
DOI: 10.3390/v16050724 -
Journal of Medical Virology Jul 2023Despite the extensive use of effective vaccines and antiviral drugs, chronic hepatitis B virus (HBV) infection continues to pose a serious threat to global public...
Despite the extensive use of effective vaccines and antiviral drugs, chronic hepatitis B virus (HBV) infection continues to pose a serious threat to global public health. Therapies with novel mechanisms of action against HBV are being explored for achieving a functional cure. In this study, five murine models of HBV replication were used to investigate the inhibitory effect of RNA binding motif protein 24 (RBM24) on HBV replication. The findings revealed that RBM24 serves as a host restriction factor and suppresses HBV replication in vivo. The transient overexpression of RBM24 in hydrodynamics-based mouse models of HBV replication driven by the CMV or HBV promoters suppressed HBV replication. Additionally, the ectopic expression of RBM24 decreased viral accumulation and the levels of HBV covalently closed circular DNA (cccDNA) in an rcccDNA mouse model. The liver-directed transduction of adeno-associated viruses (AAV)-RBM24 mediated the stable hepatic expression of RBM24 in pAAV-HBV1.2 and HBV/tg mouse models, and markedly reduced the levels of HBV cccDNA and other viral indicators. Altogether, these findings revealed that RBM24 inhibits the replication of HBV in vivo, and RBM24 may be a potential therapeutic target for combating HBV infections.
Topics: Mice; Animals; Hepatitis B virus; Hepatitis B, Chronic; Virus Replication; Hepatitis B; DNA, Circular; RNA-Binding Motifs; DNA, Viral
PubMed: 37485644
DOI: 10.1002/jmv.28969 -
Journal of the American Academy of... Oct 2023
Topics: Humans; Psoriasis; Hepatitis B virus; Hepatitis B; Vaccination; Biological Products
PubMed: 37343831
DOI: 10.1016/j.jaad.2023.06.023 -
Journal of Medical Virology Oct 2023Chronic infection of hepatitis B virus (HBV) is the major cause of hepatocellular carcinoma (HCC). Notably, 90% of HBV-positive HCC cases exhibit detectable HBV...
Chronic infection of hepatitis B virus (HBV) is the major cause of hepatocellular carcinoma (HCC). Notably, 90% of HBV-positive HCC cases exhibit detectable HBV integrations, hinting at the potential early entanglement of these viral integrations in tumorigenesis and their subsequent oncogenic implications. Nevertheless, the precise chronology of integration events during HCC tumorigenesis, alongside their sequential structural patterns, has remained elusive thus far. In this study, we applied whole-genome sequencing to multiple biopsies extracted from six HBV-positive HCC cases. Through this approach, we identified point mutations and viral integrations, offering a blueprint for the intricate tumor phylogeny of these samples. The emergent narrative paints a rich tapestry of diverse evolutionary trajectories characterizing the analyzed tumors. We uncovered oncogenic integration events in some samples that appear to happen before and during the initiation stage of tumor development based on their locations in reconstituted trajectories. Furthermore, we conducted additional long-read sequencing of selected samples and unveiled integration-bridged chromosome rearrangements and tandem repeats of the HBV sequence within integrations. In summary, this study revealed premalignant oncogenic and sequential complex integrations and highlighted the contributions of HBV integrations to HCC development and genome instability.
Topics: Humans; Carcinoma, Hepatocellular; Hepatitis B virus; Liver Neoplasms; Carcinogenesis; Cell Transformation, Neoplastic; Hepatitis B
PubMed: 37877809
DOI: 10.1002/jmv.29187 -
Journal of Dental Research Oct 2023Hepatitis delta virus (HDV) has been detected in the minor salivary gland (MSG) tissue of Sjögren's disease (SjD) patients in the absence of a hepatitis B virus (HBV)...
Hepatitis delta virus (HDV) has been detected in the minor salivary gland (MSG) tissue of Sjögren's disease (SjD) patients in the absence of a hepatitis B virus (HBV) coinfection. Previous research has shown that HDV antigen (HDAg) expression can trigger an SjD-like phenotype in vivo, demonstrating a potential cause-and-effect relationship. We hypothesize that if HDV plays a role in the development of SjD, then HDV profiles may be correlated with disease manifestations. This retrospective study characterized HDV in a cohort of 48 SjD MSG samples collected between 2014 and 2021. Analyses of HDAg expression, including cell type and subcellular localization, in situ hybridization of HDV RNA, and comparative analyses with associated SjD and viral hepatitis clinical features, were conducted. HDAg was detected in MSG acinar, ductal, myoepithelial, and adipose cells and localized with the nuclei, cytoplasm, and mitochondria. In situ hybridization detected HDV genomic RNA localization in the MSG nuclei. A significant negative correlation was found between HDAg intensity and focal lymphocytic inflammation and in patients with both anti-SSA/Ro-52 and anti-SSA/Ro-60. In analyzing autoimmune disease comorbidities with SjD, it was found that SjD patients diagnosed with autoimmune thyroiditis and/or hypothyroidism were significantly more represented in the high HDAg intensity group compared to the negative and moderate HDAg intensity groups. No significant associations were detected between MSG-localized HDAg and liver enzymes or an evident HBV coinfection. This study has further confirmed that there is a nonhepatic reservoir for chronic HDV persistence in SjD-affected salivary gland tissue in a third independent SjD patient cohort. In addition, this study describes the unique colocalization of HDAg with mitochondria. The detection of HDV antigen and sequence within SjD-affected salivary gland tissue, and in the absence of an evident current or past HBV coinfection, warrants further investigation.
Topics: Humans; Hepatitis Delta Virus; Hepatitis delta Antigens; Retrospective Studies; Coinfection; Salivary Glands, Minor; Hepatitis B; Hepatitis B virus; Sjogren's Syndrome; RNA
PubMed: 37575047
DOI: 10.1177/00220345231186394 -
Saudi Journal of Gastroenterology :... Mar 2024A substantial proportion of patients with chronic hepatitis B (CHB) do not fall into any of the defined phases and are considered to be in the "gray zone" or...
A substantial proportion of patients with chronic hepatitis B (CHB) do not fall into any of the defined phases and are considered to be in the "gray zone" or "indeterminate phase." Most of the current clinical practice guidelines have no recommendations for antiviral treatment for them. However, the gray zone CHB patients with significant hepatitis B virus levels (>2000 IU/mL) and persistently normal alanine aminotransferase (ALT) levels have a significantly high risk of hepatic inflammation, fibrosis, and hepatocellular carcinoma. The molecular, clinical, and economic data that we have reviewed collectively in this article provide support for simplification of treatment initiation strategies that incorporate broader treatment of adult patients with CHB in the gray zone (hepatitis B virus [HBV] DNA ≥2000 IU/mL), regardless of ALT levels.
Topics: Adult; Humans; Hepatitis B virus; Hepatitis B; Alanine Transaminase; Carcinoma, Hepatocellular; Liver Neoplasms
PubMed: 37843134
DOI: 10.4103/sjg.sjg_279_23 -
Journal of Virology Oct 2023Hepatitis B virus cccDNA is the key target for the necessary development of antiviral therapies aimed at curing chronic hepatitis B. The CRISPR-based system to produce...
Hepatitis B virus cccDNA is the key target for the necessary development of antiviral therapies aimed at curing chronic hepatitis B. The CRISPR-based system to produce covalently closed circular (cccDNA)-like extrachromosomal DNAs described in this report enables large-scale screens of chemical libraries to identify drug candidates with the potential to permanently inactivate cccDNA. Moreover, this approach permits investigations on unresolved problems as described in this report concerning cccDNA biology including mechanisms of SMC5/6-dependent transcriptional silencing and the contributions of the SMC5/6 complex to cccDNA stability in resting and dividing hepatocytes.
Topics: Humans; DNA, Circular; DNA, Viral; Hepatitis B virus; Hepatitis B, Chronic; Virus Replication; CRISPR-Cas Systems
PubMed: 37819132
DOI: 10.1128/jvi.01185-23