scholarly journals ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection upon DNA Damage

Viruses ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 997 ◽  
Author(s):  
Anastasiya Kostyusheva ◽  
Sergey Brezgin ◽  
Ekaterina Bayurova ◽  
Ilya Gordeychuk ◽  
Maria Isaguliants ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Dna Damage ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hbv Infection ◽  
Hbv Reactivation ◽  
Mrna Levels ◽  
Hbv Replication ◽  
Chronic Hepatitis B Virus ◽  
B Virus

Chronic hepatitis B virus infection (CHB) caused by the hepatitis B virus (HBV) is one of the most common viral infections in the world. Reactivation of HBV infection is a life-threatening condition observed in patients with CHB receiving chemotherapy or other medications. Although HBV reactivation is commonly attributed to immune suppression, other factors have long been suspected to play a role, including intracellular signaling activated in response to DNA damage. We investigated the effects of DNA-damaging factors (doxorubicin and hydrogen peroxide) on HBV reactivation/replication and the consequent DNA-damage response. Dose-dependent activation of HBV replication was observed in response to doxorubicin and hydrogen peroxide which was associated with a marked elevation in the mRNA levels of ataxia-telangiectasia mutated (ATM) and ATM- and RAD3-related (ATR) kinases. Downregulation of ATM or ATR expression by shRNAs substantially reduced the levels of HBV RNAs and DNA. In contrast, transcriptional activation of ATM or ATR using CRISPRa significantly increased HBV replication. We conclude that ATM and ATR are essential for HBV replication. Furthermore, DNA damage leading to the activation of ATM and ATR transcription, results in the reactivation of HBV replication.

scholarly journals Transcriptional Elongation Control of Hepatitis B Virus Covalently Closed Circular DNA Transcription by Super Elongation Complex and BRD4

2017 ◽  
Vol 37 (19) ◽  
Author(s):  
Joel Celio Francisco ◽  
Qian Dai ◽  
Zhuojuan Luo ◽  
Yan Wang ◽  
Roxanne Hui-Heng Chong ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hbv Infection ◽  
Intermediate Step ◽  
Hbv Reactivation ◽  
Transcriptional Elongation ◽  
Elongation Complex ◽  
Super Elongation Complex ◽  
Chronic Hepatitis B Virus ◽  
B Virus

ABSTRACT Chronic hepatitis B virus (HBV) infection can lead to liver cirrhosis and hepatocellular carcinoma. HBV reactivation during or after chemotherapy is a potentially fatal complication for cancer patients with chronic HBV infection. Transcription of HBV is a critical intermediate step of the HBV life cycle. However, factors controlling HBV transcription remain largely unknown. Here, we found that different P-TEFb complexes are involved in the transcription of the HBV viral genome. Both BRD4 and the super elongation complex (SEC) bind to the HBV genome. The treatment of bromodomain inhibitor JQ1 stimulates HBV transcription and increases the occupancy of BRD4 on the HBV genome, suggesting the bromodomain-independent recruitment of BRD4 to the HBV genome. JQ1 also leads to the increased binding of SEC to the HBV genome, and SEC is required for JQ1-induced HBV transcription. These findings reveal a novel mechanism by which the HBV genome hijacks the host P-TEFb-containing complexes to promote its own transcription. Our findings also point out an important clinical implication, that is, the potential risk of HBV reactivation during therapy with a BRD4 inhibitor, such as JQ1 or its analogues, which are a potential treatment for acute myeloid leukemia.

New insight in the pathobiology of hepatitis B virus infection

Gut ◽  
2012 ◽  
Vol 61 (Suppl 1) ◽  
pp. i6-i17 ◽  
Author(s):  
Maura Dandri ◽  
Stephen Locarnini
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Immune Responses ◽  
Current Knowledge ◽  
Hbv Infection ◽  
Infected Hepatocyte ◽  
Hbv Replication ◽  
Chronic Hepatitis B Virus ◽  
B Virus ◽  
Important Host

Chronic hepatitis B virus (HBV) infection remains a major health burden and the main risk factor for the development of hepatocellular carcinoma worldwide. However, HBV is not directly cytopathic and liver injury appears to be mostly caused by repeated attempts of the host's immune responses to control the infection. Recent studies have shown that the unique replication strategy adopted by HBV enables it to survive within the infected hepatocyte while complex virus–host interplays ensure the virus is able to fulfil its replication requirements yet is still able to evade important host antiviral innate immune responses. Clearer understanding of the host and viral mechanisms affecting HBV replication and persistence is necessary to design more effective therapeutic strategies aimed at improving the management of patients with chronic HBV infection to eventually achieve viral eradication. This article focuses on summarising the current knowledge of factors influencing the course of HBV infection, giving emphasis on the use of novel assays and quantitative serological and intrahepatic biomarkers as tools for predicting treatment response and disease progression.

scholarly journals Interactions between hepatitis B virus and aflatoxin B1: effects on p53 induction in HepaRG cells

2012 ◽  
Vol 93 (3) ◽  
pp. 640-650 ◽  
Author(s):  
Myriam Lereau ◽  
Doriane Gouas ◽  
Stéphanie Villar ◽  
Ahmad Besaratinia ◽  
Agnès Hautefeuille ◽  
...  
Keyword(s):  
Risk Factors ◽  
Dna Damage ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Cell Line ◽  
Hbv Infection ◽  
Hbv Replication ◽  
Heparg Cell Line ◽  
Heparg Cells ◽  
B Virus

Infection by hepatitis B virus (HBV) and dietary exposure to aflatoxin B1 (AFB1) are the main risk factors for the development of chronic liver disease and hepatocellular carcinoma (HCC). How these factors cooperate is still largely unknown. AFB1 activation leads to DNA adduction and mutagenesis, with a specific mutation at codon 249 in TP53 (p.R249S). So far, only limited studies have addressed the effects of AFB1 on HBV replication. We have analysed the effects of both risk factors on p53 induction during HBV infection in HepaRG, a cell line with hepatocyte-like morphology that metabolizes AFB1 and supports HBV infection. Exposure to AFB1 up to 5 µM induced a downregulation of HBV replication after 48 h, as measured by a decrease in viral antigens in the culture medium (HBsAg, HBeAg and large envelope protein) and in intracellular levels of HBV transcripts, DNA and HBsAg. Conversely, HBV infection did not significantly modify AFB1-DNA adduct formation or repair as assessed by immunodot-blot assay, and the induction of p53 in response to AFB1 was similar in infected and non-infected HepaRG cells. Overall, our results suggest that AFB1 exposure decreases HBV replication, whereas DNA damage by AFB1 and subsequent p53 induction is not affected by the presence of the virus. Thus, in HepaRG cell line, AFB1 and HBV do not cooperate to increase DNA damage by AFB1. Further studies on the effects of both factors in a context of chronicity are needed to better understand synergistic effects.

scholarly journals Treatment or Prophylaxis against Hepatitis B Virus Infection in Patients with Rheumatic Disease Undergoing Immunosuppressive Therapy: An Update

2021 ◽  
Vol 10 (12) ◽  
pp. 2564
Author(s):  
Cristina Stasi ◽  
Giacomo Tiengo ◽  
Sinan Sadalla ◽  
Anna Linda Zignego
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Immunosuppressive Therapy ◽  
Antiviral Treatment ◽  
Hbv Infection ◽  
Hbv Reactivation ◽  
Close Monitoring ◽  
Occult Hbv ◽  
Chronic Hepatitis B Virus ◽  
B Virus

Chronic hepatitis B virus (HBV) flares or reactivations are serious causes of morbidity or mortality in rheumatologic patients undergoing immunosuppressive therapy. The recent insights in the pathogenesis of rheumatic diseases led to the use of new immunosuppressive therapies indicated in case of failure, partial response, or intolerance of conventional synthetic disease-modifying anti-rheumatic drugs. Based on these premises, this review examines and discusses the main rheumatologic treatments that could require the initiation of prophylactic treatment or close monitoring of occult HBV infection in patients beginning antiviral therapy at the first signs of HBV reactivation, or antiviral treatment in chronic HBV-infected patients. We searched for relevant studies published in the last five years. Studies suggested that the presence of HBV infection is common in rheumatic patients and HBV reactivation during these immunosuppressant treatments is quite frequent in these kinds of patients. Therefore, before starting an immunosuppressive therapy, patients should be screened for HBsAg, anti-HBs, and anti-HBc and, on the basis of markers positivity, they should be carefully characterized for HBV infection phases. In conclusion, screening of HBV infection in patients undergoing immunosuppressive therapy with subsequent HBV monitoring, prophylaxis or treatment consistently reduces the risk of clinical consequences.

scholarly journals Stimulated phospholipid synthesis is key for hepatitis B virus replications

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Qingxia Huang ◽  
Hehua Lei ◽  
Laifeng Ding ◽  
Yulan Wang
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hbv Infection ◽  
High Morbidity ◽  
Phospholipid Synthesis ◽  
Liquid Chromatograph ◽  
Hbv Replication ◽  
Chronic Hepatitis B Virus ◽  
B Virus ◽  
The Relationship

Abstract Chronic hepatitis B Virus (HBV) infection has high morbidity, high pathogenicity and unclear pathogenesis. To elucidate the relationship between HBV replication and host phospholipid metabolites, we measured 10 classes of phospholipids in serum of HBV infected patients and cells using ultra performance liquid chromatograph-triple quadruple mass spectrometry. We found that the levels of phosphatidylcholine (PC), phosphatidylethanolamine, and lyso-phosphatidic acid were increased in HBsAg (+) serum of infected patients compared with HBsAg (−), while phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, and sphingomyelin were decreased, which were confirmed in an HBV infected HepG2.2.15 cell line. We further evaluated the enzyme levels of PC pathways and found that PCYT1A and LPP1 for PC synthesis were up-regulated after HBV infection. Moreover, HBV replication was inhibited when PCYT1A and LPP1 were inhibited. These results indicated that the PC synthesis in HBV infected host are regulated by PCYT1A and LPP1, which suggests that PCYT1A, LPP1 could be new potential targets for HBV treatment.

High prevalence of occult hepatitis C virus infection in patients with chronic hepatitis B virus infection

2013 ◽  
Vol 62 (8) ◽  
pp. 1235-1238 ◽  
Author(s):  
Inmaculada Castillo ◽  
Javier Bartolomé ◽  
Juan Antonio Quiroga ◽  
Vicente Carreño
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Hepatitis B Virus ◽  
Virus Infection ◽  
Hepatitis B ◽  
Hcv Infection ◽  
Hbv Infection ◽  
Chronic Hepatitis B Virus ◽  
B Virus

Hepatitis C virus (HCV) infection in the absence of detectable antibodies against HCV and of viral RNA in serum is called occult HCV infection. Its prevalence and clinical significance in chronic hepatitis B virus (HBV) infection is unknown. HCV RNA was tested for in the liver samples of 52 patients with chronic HBV infection and 21 (40 %) of them were positive for viral RNA (occult HCV infection). Liver fibrosis was found more frequently and the fibrosis score was significantly higher in patients with occult HCV than in negative ones, suggesting that occult HCV infection may have an impact on the clinical course of HBV infection.

scholarly journals Creation of a Six-fingered Artificial Transcription Factor That Represses the Hepatitis B Virus HBx Gene Integrated into a Human Hepatocellular Carcinoma Cell Line

2012 ◽  
Vol 18 (4) ◽  
pp. 378-387 ◽  
Author(s):  
Xinghui Zhao ◽  
Zhanzhong Zhao ◽  
Junwei Guo ◽  
Peitang Huang ◽  
Xudong Zhu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Transcription Factor ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Cell Line ◽  
Hbv Infection ◽  
Luciferase Reporter ◽  
Artificial Transcription Factor ◽  
Chronic Hepatitis B Virus ◽  
B Virus

Chronic hepatitis B virus (HBV) infection is an independent risk factor for the development of hepatocellular carcinoma (HCC). The HBV HBx gene is frequently identified as an integrant in the chromosomal DNA of patients with HCC. HBx encodes the X protein (HBx), a putative viral oncoprotein that affects transcriptional regulation of several cellular genes. Therefore, HBx may be an ideal target to impede the progression of HBV infection–related HCC. In this study, integrated HBx was transcriptionally downregulated using an artificial transcription factor (ATF). Two three-fingered Cys2-His2 zinc finger (ZF) motifs that specifically recognized two 9-bp DNA sequences regulating HBx expression were identified from a phage-display library. The ZF domains were linked into a six-fingered protein that specified an 18-bp DNA target in the Enhancer I region upstream of HBx. This DNA-binding domain was fused with a Krüppel-associated box (KRAB) transcriptional repression domain to produce an ATF designed to downregulate HBx integrated into the Hep3B HCC cell line. The ATF significantly repressed HBx in a luciferase reporter assay. Stably expressing the ATF in Hep3B cells resulted in significant growth arrest, whereas stably expressing the ATF in an HCC cell line lacking integrated HBx (HepG2) had virtually no effect. The targeted downregulation of integrated HBx is a promising novel approach to inhibiting the progression of HBV infection–related HCC.

Discovery of novel hepatitis B virus (HBV) antivirals and analysis of mechanisms of action of HBV-targeting agents

2017 ◽  
Author(s):  
◽  
Andrew Douglas Huber
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Treatment Options ◽  
Mechanisms Of Action ◽  
Hbv Infection ◽  
Viral Inhibition ◽  
University Of Missouri ◽  
Chronic Hepatitis B Virus ◽  
B Virus

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Chronic hepatitis B virus (HBV) infection leads to liver disease, cirrhosis, and hepatocellular carcinoma. Globally, an estimated 50% of all hepatocellular carcinoma cases are linked to chronic HBV infection. More than 240 million people are chronically infected, and there are 0.5-1 million deaths per year due to HBVrelated liver conditions. HBV treatment options rarely cure infections and are associated with adverse side effects that often outweigh the potential benefits of treatment. New treatments, therefore, are highly desired for HBV therapy. Towards this goal, we have developed novel compounds targeting two viral targets and assessed the mechanisms of action by which these compounds act. We have developed systems for the discovery and evaluation of compounds that inhibit 2 distinct steps in the HBV life cycle. Using these systems, we have developed potent inhibitors of HBV replication that have potential to become clinically used HBV drugs. Furthermore, we have used our methods to evaluate which properties of these compounds are likely to result in better viral inhibition. The work described in this thesis has led to at least 2 new compound groups for potential use as HBV antivirals and provides insight into mechanisms by which potent antivirals can be achieved.

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