scholarly journals Large scaled analysis of hepatitis B virus (HBV) DNA integration in HBV related hepatocellular carcinomas

Gut ◽  
2005 ◽  
Vol 54 (8) ◽  
pp. 1162-1168 ◽  
Author(s):  
Y Murakami
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hbv Dna ◽  
Dna Integration ◽  
Hepatocellular Carcinomas ◽  
B Virus ◽  
Hbv Dna Integration

scholarly journals Hepatitis B Virus DNA Integration Occurs Early in the Viral Life Cycle in anIn VitroInfection Model via Sodium Taurocholate Cotransporting Polypeptide-Dependent Uptake of Enveloped Virus Particles

2018 ◽  
Vol 92 (11) ◽  
pp. e02007-17 ◽  
Author(s):  
Thomas Tu ◽  
Magdalena A. Budzinska ◽  
Florian W. R. Vondran ◽  
Nicholas A. Shackel ◽  
Stephan Urban
Keyword(s):  
Hepatitis B Virus ◽  
Liver Cancer ◽  
Hepatitis B ◽  
Chronic Infection ◽  
Hbv Dna ◽  
Hbv Infection ◽  
Dna Integration ◽  
B Virus ◽  
Hbv Dna Integration

ABSTRACTChronic infection by hepatitis B virus (HBV) is the major contributor to liver disease worldwide. Though HBV replicates via a nuclear episomal DNA (covalently closed circular DNA [cccDNA]), integration of HBV DNA into the host cell genome is regularly observed in the liver in infected patients. While reported as a prooncogenic alteration, the mechanism(s) and timing of HBV DNA integration are not well understood, chiefly due to the lack ofin vitroinfection models that have detectable integration events. In this study, we have established anin vitrosystem in which integration can be reliably detected following HBV infection. We measured HBV DNA integration using inverse nested PCR in primary human hepatocytes, HepaRG-NTCP, HepG2-NTCP, and Huh7-NTCP cells after HBV infection. Integration was detected in all cell types at a rate of >1 per 10,000 cells, with the most consistent detection in Huh7-NTCP cells. The integration rate remained stable between 3 and 9 days postinfection. HBV DNA integration was efficiently blocked by treatment with a 200 nM concentration of the HBV entry inhibitor Myrcludex B, but not with 10 μM tenofovir, 100 U of interferon alpha, or a 1 μM concentration of the capsid assembly inhibitor GLS4. This suggests that integration of HBV DNA occurs immediately after infection of hepatocytes and is likely independent ofde novoHBV genome replication in this model. Site analysis revealed that HBV DNA integrations were distributed over the entire human genome. Further, integrated HBV DNA sequences were consistent with double-stranded linear HBV DNA being the major precursor. Thus, we have established anin vitrosystem to interrogate the mechanisms of HBV DNA integration.IMPORTANCEHepatitis B virus (HBV) is a common blood-borne pathogen and, following a chronic infection, can cause liver cancer and liver cirrhosis. Integration of HBV DNA into the host genome occurs in all known members of theHepadnaviridaefamily, despite this form not being necessary for viral replication. HBV DNA integration has been reported to drive liver cancer formation and persistence of virus infection. However, when and the mechanism(s) by which HBV DNA integration occurs are not clear. In this study, we have developed and characterized anin vitrosystem to reliably detect HBV DNA integrations that result from a true HBV infection event and that closely resemble those found in patient tissues. Using this model, we showed that integration occurs when the infection is first established. Importantly, we provide here a system to analyze molecular factors involved in HBV integration, which can be used to develop strategies to halt its formation.

scholarly journals Hepatitis B virus (HBV) DNA integration in patients with occult HBV infection and hepatocellular carcinoma

2015 ◽  
Vol 35 (10) ◽  
pp. 2311-2317 ◽  
Author(s):  
Carlo Saitta ◽  
Gianluca Tripodi ◽  
Adalberto Barbera ◽  
Antonio Bertuccio ◽  
Antonina Smedile ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hbv Dna ◽  
Hbv Infection ◽  
Occult Hbv Infection ◽  
Dna Integration ◽  
Occult Hbv ◽  
B Virus ◽  
Hbv Dna Integration

Hepatitis B virus (HBV) DNA integration is not driven by viral proteins

2019 ◽  
Author(s):  
T Tu ◽  
B Zehnder ◽  
M Levy ◽  
G Micali ◽  
L Tran ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Viral Proteins ◽  
Hbv Dna ◽  
Dna Integration ◽  
B Virus ◽  
Hbv Dna Integration

scholarly journals Hepatitis B Virus DNA Integration, Chronic Infections and Hepatocellular Carcinoma

2021 ◽  
Vol 9 (8) ◽  
pp. 1787
Author(s):  
Maria Bousali ◽  
George Papatheodoridis ◽  
Dimitrios Paraskevis ◽  
Timokratis Karamitros
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Molecular Mechanisms ◽  
Horizontal Transmission ◽  
Acute Infection ◽  
Hbv Dna ◽  
Clinical Aspects ◽  
Dna Integration ◽  
B Virus ◽  
Hbv Dna Integration

Hepatitis B Virus (HBV) is an Old World virus with a high mutation rate, which puts its origins in Africa alongside the origins of Homo sapiens, and is a member of the Hepadnaviridae family that is characterized by a unique viral replication cycle. It targets human hepatocytes and can lead to chronic HBV infection either after acute infection via horizontal transmission usually during infancy or childhood or via maternal–fetal transmission. HBV has been found in ~85% of HBV-related Hepatocellular Carcinomas (HCC), and it can integrate the whole or part of its genome into the host genomic DNA. The molecular mechanisms involved in the HBV DNA integration is not yet clear; thus, multiple models have been described with respect to either the relaxed-circular DNA (rcDNA) or the double-stranded linear DNA (dslDNA) of HBV. Various genes have been found to be affected by HBV DNA integration, including cell-proliferation-related genes, oncogenes and long non-coding RNA genes (lincRNAs). The present review summarizes the advances in the research of HBV DNA integration, focusing on the evolutionary and molecular side of the integration events along with the arising clinical aspects in the light of WHO’s commitment to eliminate HBV and viral hepatitis by 2030.

scholarly journals Cellular Genomic Sites of Hepatitis B Virus DNA Integration

Genes ◽  
2018 ◽  
Vol 9 (7) ◽  
pp. 365 ◽  
Author(s):  
Magdalena A. Budzinska ◽  
Nicholas A. Shackel ◽  
Stephan Urban ◽  
Thomas Tu
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Insertional Mutagenesis ◽  
Current Knowledge ◽  
Hbv Dna ◽  
Dna Integration ◽  
Open Questions ◽  
Cellular Genes ◽  
B Virus ◽  
Hbv Dna Integration

Infection with the Hepatitis B Virus (HBV) is one of the strongest risk-factors for liver cancer (hepatocellular carcinoma, HCC). One of the reported drivers of HCC is the integration of HBV DNA into the host cell genome, which may induce pro-carcinogenic pathways. These reported pathways include: induction of chromosomal instability; generation of insertional mutagenesis in key cancer-associated genes; transcription of downstream cancer-associated cellular genes; and/or formation of a persistent source of viral protein expression (particularly HBV surface and X proteins). The contribution of each of these specific mechanisms towards carcinogenesis is currently unclear. Here, we review the current knowledge of specific sites of HBV DNA integration into the host genome, which sheds light on these mechanisms. We give an overview of previously-used methods to detect HBV DNA integration and the enrichment of integration events in specific functional and structural cellular genomic sites. Finally, we posit a theoretical model of HBV DNA integration during disease progression and highlight open questions in the field.

Hepatitis B virus DNA integration in hepatocellular carcinomas and their adjacent non-neoplastic liver tissues.

1989 ◽  
Vol 38 (4) ◽  
pp. 443-453
Author(s):  
Jing-juan Ding ◽  
Hidetsugu Saito ◽  
Toshio Morizane ◽  
Tatehiro Kagawa ◽  
Shingo Matsumoto ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hepatitis B Virus Dna ◽  
Dna Integration ◽  
Hepatocellular Carcinomas ◽  
B Virus ◽  
Liver Tissues

scholarly journals Hepatitis B Virus DNA Integration: In Vitro Models for Investigating Viral Pathogenesis and Persistence

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 180
Author(s):  
Thomas Tu ◽  
Henrik Zhang ◽  
Stephan Urban
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
In Vitro Models ◽  
Hbv Dna ◽  
Hbv Infection ◽  
Dna Integration ◽  
B Virus ◽  
Chronic Hbv ◽  
Globally Distributed

Hepatitis B virus (HBV) is a globally-distributed pathogen and is a major cause of liver disease. HBV (or closely-related animal hepadnaviruses) can integrate into the host genome, but (unlike retroviruses) this integrated form is replication-defective. The specific role(s) of the integrated HBV DNA has been a long-standing topic of debate. Novel in vitro models of HBV infection combined with sensitive molecular assays now enable researchers to investigate this under-characterised phenomenon with greater ease and precision. This review covers the contributions these systems have made to understanding how HBV DNA integration induces liver cancer and facilitates viral persistence. We summarise the current findings into a working model of chronic HBV infection and discuss the clinical implications of this hypothetical framework on the upcoming therapeutic strategies used to curb HBV-associated pathogenesis.

272 Use of LioCyx-M, autologous hepatitis B virus (HBV)-Specific T cell receptor (TCR) T-cells, in advanced HBV-related hepatocellular carcinoma (HCC)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A297-A297
Author(s):  
Fu-Sheng Wang ◽  
Fanping Meng ◽  
Jiehua Jin ◽  
Yuanyuan Li ◽  
Regina Wanju Wong ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Hepatitis B Virus ◽  
T Cell ◽  
Hepatitis B ◽  
T Cell Receptor ◽  
Dose Level ◽  
Cell Receptor ◽  
Hbv Dna ◽  
B Virus

BackgroundWe have demonstrated the ability of Hepatitis-B-virus (HBV)-specific T cell receptor (TCR) bioengineered T cells to recognize and lyse Hepatocellular carcinoma (HCC) cells expressing HBV antigens derived from HBV-DNA integration in patients with liver transplant.1 LioCyx-M is an immunotherapeutic product composing of autologous T cells transiently modified with in-vitro transcribed mRNA encoding HBV-specific TCR. The transient TCR expression makes LioCyx -M amenable to a dose escalating posology.MethodsThe primary endpoint of this phase 1 trial is to assess the safety and tolerability of LioCyx-M in patients with advanced HBV-HCC without curative treatment options. Eligible patients were diagnosed with Barcelona clinic liver cancer stage B or C HCC (Child-Pugh < 7 points), receiving >1 year antiviral treatment prior to enrollment. These patients had matching HLA class I genotypes which present HBV encoded antigen. Peripheral blood was collected from each patient prior to each dose for LioCyx-M manufacturing. Patients received 4 escalating doses of 1×104 cells/kg, 1×105 cells/kg, 1×106 cells/kg, 5×106 cells/kg bodyweight (BW) in the first treatment cycle, each intravenously administered weekly. Patients underwent 1-month safety assessment post the 4th infusion, according to Common Terminology NCI CTCAE Version 4.0.3. If there were no dose associated toxicities, patients were eligible to continue administration of LioCyx-M at dose of 5 × 106 cells/kg BW weekly. Tumor response per RECIST 1.1 criteria and survival time were assessed.ResultsAt data cutoff (30 April 2020), eight patients were enrolled, with a median age of 53 (range: 49 - 67). These patients received a median number of 6 (range: 4 - 12) infusions of LioCyx-M. 1 patient developed Grade 3 elevations in alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST) and bilirubin after receiving LioCyx-M at dose level of 1×105 cells/kg BW. Another patient had Grade 1 transient fever after receiving LioCyx-M at dose level 5×106 cells/kg BW in the 4th, 5th and 6th infusions. No treatment-related adverse events (trAEs) such as cytokine release syndrome or neurotoxicity were observed. No fatal trAEs were observed. The median time to progression was 1.9 months (range: 0.2 - 9.5 months). The median overall survival was 34 months (range: 3 - 38.2 months).ConclusionsThe encouraging clinical outcome and tolerable safety highlight the good benefit-risk profile of LioCyx-M. Therefore, further exploration of efficacy of LioCyx-M treatment for advanced HBV-HCC is warranted in a Phase 2 proof-of-concept clinical study.AcknowledgementsFunding: Lion TCR.Trial RegistrationNCT03899415Ethics ApprovalThe study was approved by Fifth Medical Center of Chinese PLA General Hospital’s Ethics Board, approval number R2016185DI010.ReferenceTan AT, Yang N, Lee Krishnamoorthy T, et al. Use of Expression Profiles of HBV-DNA Integrated Into Genomes of Hepatocellular Carcinoma Cells to Select T Cells for Immunotherapy. Gastroenterology 2019;156(6):1862–1876.e9.

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