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

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.

Download Full-text

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

Journal of Clinical Medicine ◽

10.3390/jcm10122564 ◽

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.

Download Full-text

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

Viruses ◽

10.3390/v11110997 ◽

2019 ◽

Vol 11 (11) ◽

pp. 997 ◽

Cited By ~ 3

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.

Download Full-text

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

Journal of Medical Microbiology ◽

10.1099/jmm.0.058297-0 ◽

2013 ◽

Vol 62 (8) ◽

pp. 1235-1238 ◽

Cited By ~ 6

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.

Download Full-text

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

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057112463066 ◽

2012 ◽

Vol 18 (4) ◽

pp. 378-387 ◽

Cited By ~ 7

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.

Download Full-text

What are the effects of Radix Sophorae Flavescentis in people with chronic hepatitis B virus (HBV) infection?

Cochrane Clinical Answers ◽

10.1002/cca.2599 ◽

2019 ◽

Author(s):

Jane Burch ◽

Deepak Singh-Ranger

Keyword(s):

Chronic Hepatitis ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Chronic Hepatitis B ◽

Hbv Infection ◽

Chronic Hepatitis B Virus ◽

B Virus

Download Full-text

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

10.32469/10355/70421 ◽

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.

Download Full-text

Rituximab increases the risk of hepatitis B virus reactivation in non-Hodgkin lymphoma patients who are hepatitis B surface antigen-positive or have resolved hepatitis B virus infection in a real-world setting: a retrospective study

PeerJ ◽

10.7717/peerj.7481 ◽

2019 ◽

Vol 7 ◽

pp. e7481 ◽

Cited By ~ 5

Author(s):

Yu-Fen Tsai ◽

Ching-I Yang ◽

Jeng-Shiun Du ◽

Ming-Hui Lin ◽

Shih-Hao Tang ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Hodgkin Lymphoma ◽

Hepatitis B Surface Antigen ◽

Hbv Infection ◽

Hbv Reactivation ◽

Virus Reactivation ◽

Non Hodgkin Lymphoma ◽

B Virus ◽

Hepatitis Flare

Background Hepatitis B virus (HBV) reactivation with a hepatitis flare is a common complication in lymphoma patients treated with immunotherapy and/or chemotherapy. Anti-HBV prophylaxis is suggested for non-Hodgkin lymphoma (NHL) patients undergoing rituximab therapy, even those with resolved HBV infection. Since anti-HBV prophylaxis for patients with resolved HBV infection is not covered by national health insurance in Taiwan, a proportion of these patients receive no prophylaxis. In addition, late HBV reactivation has emerged as a new issue in recent reports, and no consensus has been reached for the optimal duration of antiviral prophylaxis. Thus, the aim of our study was to investigate the incidence and outcomes of HBV reactivation in NHL patients in a real-world setting and to study the frequency of late HBV reactivation. Materials Non-Hodgkin lymphoma patients who received rituximab and/or chemotherapy at our institute between January 2011 and December 2015 and who were hepatitis B surface antigen (HBsAg)- or hepatitis B core antibody (HBcAb)-positive were reviewed retrospectively. Results A total of 388 patients were screened between January 2011 and December 2015. In total, 196 patients were excluded because HBsAg was not assessed, HBcAb was negative or not assessed, or they were not treated with immunosuppressive therapy. Finally, the retrospective study included 62 HBsAg-positive NHL patients and 130 NHL patients with resolved HBV infection (HBsAg-negative and HBcAb-positive). During a median 30.5-month follow-up period, seven patients experienced HBV reactivation, five of whom had a hepatitis flare. The incidence of HBV reactivation did not significantly differ between the HBsAg-positive patients and the resolved HBV infection population without anti-HBV prophylaxis (4.8% vs. 3.1%, P = 0.683). All patients with HBV reactivation were exposed to rituximab. Notably, late HBV reactivation was not uncommon (two of seven patients with HBV reactivation events, 28.6%). Hepatitis B virus reactivation did not influence the patients’ overall survival. An age ≥65 years and an advanced disease stage were independent risk factors for poorer overall survival. Conclusion The incidence of HBV reactivation was similar between the HBsAg-positive patients with antiviral prophylaxis and the resolved HBV infection population without anti-HBV prophylaxis. All HBV reactivation events occurred in NHL patients exposed to rituximab. Late reactivation was not uncommon. The duration of regular liver function monitoring for more than 1 year after immunosuppressive therapy or after withdrawal of prophylactic antiviral therapy should be prolonged. Determining the exact optimal duration of anti-HBV prophylaxis is warranted in a future prospective study for NHL patients treated with rituximab-containing therapy.

Download Full-text

Pregnancy Complicated With Hepatitis B Virus Infection and Preterm Birth: A Retrospective Cohort Study

10.21203/rs.3.rs-152431/v1 ◽

2021 ◽

Author(s):

Shuisen Zheng ◽

Huale Zhang ◽

Rongxin Chen ◽

Jianying Yan ◽

Qing Han

Keyword(s):

Risk Factor ◽

Preterm Birth ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Pregnant Women ◽

Hbv Infection ◽

Confounding Factors ◽

Logistics Regression ◽

Chronic Hepatitis B Virus ◽

B Virus

Abstract Background: We aimed to investigate whether maternal chronic hepatitis B virus (HBV) infection affects preterm birth（PTB) in pregnant women. Methods: We retrospectively analyzed HBV-infected and non-infected pregnant women attending antenatal care at Fujian Provincial Maternity and Child Health Hospital, Fuzhou, China between January 1, 2016 to December 31, 2018. Participants were divided into HBV infection (n = 1302) and control (n = 12813) groups. We compared baseline data, pregnancy and perinatal complications, and preterm delivery outcomes between groups and performed subgroup comparisons and multiple logistics regression analysis to adjust for confounding factors. Results: The incidence of PTBs before 37 weeks was similar between the groups. PTBs before 34 weeks were significantly more among the HBV infection group than among the controls (1.6% VS. 0.8% ; P = 0.003) After adjusting for confounding factors through logistics regression, HBV infection was found to be an independent PTB risk factor before 34 weeks gestation (adjusted odds ratio 1.796; 95% confidence interval[1.071, 3.012]). According to the subgroup analysis based on whether hepatitis B e-antigen (HBeAg) was positive and whether alanine aminotransferase (ALT) levels were normal during the second trimester, PTB was more frequent in HBeAg negative HBV infection before 34 weeks than among controls(1.8% VS. 0.8%). The PTB rate for pregnant women with normal ALT and HBV infection before 34 weeks was higher than that of the controls (1.6% VS. 0.8%) Conclusion HBV infection is an independent risk factor for PTB before 34 weeks. Comprehensive programs focusing on pregnant women with HBV infection would reduce the incidence of adverse outcomes.

Download Full-text