scholarly journals SIRT7 restricts HBV transcription and replication through catalyzing desuccinylation of histone H3 associated with cccDNA minichromosome

2021 ◽  
Author(s):  
Hai-Bo Yu ◽  
Sheng-Tao Cheng ◽  
Fang Ren ◽  
Yong Chen ◽  
Xiao-Feng Shi ◽  
...  
Keyword(s):  
Histone Modifications ◽  
Core Protein ◽  
Histone H3 ◽  
Viral Persistence ◽  
Hbv Infection ◽  
Public Health Burden ◽  
Hbv Cccdna ◽  
Significant Public Health ◽  
Chronic Hbv ◽  
Transcription And Replication

Chronic HBV infection is a significant public health burden worldwide. HBV cccDNA organized as a minichromosome in nucleus is responsible for viral persistence and is the key obstacle for a cure of chronic hepatitis B. Recent studies suggest cccDNA transcription is epigenetically regulated by histone modifications, especially histone acetylation and methylation. In this study, we identified transcriptionally active histone succinylation (H3K122succ) as a new histone modification on cccDNA minichromosome by using cccDNA ChIP-Seq approach. SIRT7, as a NAD+-dependent histone desuccinylase, could bind to cccDNA through interaction with HBV core protein where it catalysed histone H3K122 desuccinylation. Moreover, SIRT7 acts cooperatively with histone methyltransferase SUV39H1 and SETD2 to induce silencing of HBV transcription through modulation of chromatin structure. Our data improved the understanding of histone modifications of the cccDNA minichromosome, thus transcriptional silencing of cccDNA may represent a novel antiviral strategy for the prevention or treatment of HBV infection.

scholarly journals Cytotoxic T lymphocyte response to a wild type hepatitis B virus epitope in patients chronically infected by variant viruses carrying substitutions within the epitope.

1994 ◽  
Vol 180 (3) ◽  
pp. 933-943 ◽  
Author(s):  
A Bertoletti ◽  
A Costanzo ◽  
F V Chisari ◽  
M Levrero ◽  
M Artini ◽  
...  
Keyword(s):  
Hepatitis B ◽  
T Lymphocyte ◽  
Negative Selection ◽  
Cytotoxic T Lymphocyte ◽  
Viral Persistence ◽  
Hbv Infection ◽  
Ctl Response ◽  
B Virus ◽  
Chronic Hbv ◽  
Selection Of

Mutations that abrogate recognition of a viral epitope by class I-restricted cytotoxic T lymphocyte (CTL) can lead to viral escape if the CTL response against that epitope is crucial for viral clearance. The likelihood of this type of event is low when the CTL response is simultaneously directed against multiple viral epitopes, as has been recently reported for patients with acute self-limited hepatitis B virus (HBV) infection. The CTL response to HBV is usually quite weak, however, during chronic HBV infection, and it is generally acknowledged that this is a major determinant of viral persistence in this disease. If such individuals were to produce a mono- or oligospecific CTL response, however, negative selection of the corresponding mutant viruses might occur. We have recently studied two HLA-A2-positive patients with chronic hepatitis B who, atypically, developed a strong HLA-A2-restricted CTL response against an epitope (FLPSDFFPSV) that contains an HLA-A2-binding motif located between residues 18-27 of the viral nucleocapsid protein, hepatitis B core antigen (HBcAg). These patients failed, however, to respond to any of other HLA-A2-restricted HBV-derived peptides that are generally immunogenic in acutely infected patients who successfully clear the virus. Interestingly, DNA sequence analysis of HBV isolates from these two patients demonstrated alternative residues at position 27 (V --> A and V --> I) and position 21 (S --> N, S --> A, and S --> V) that reduced the HLA and T cell receptor-binding capacities of the variant sequences, respectively. Synthetic peptides containing these alternative sequences were poorly immunogenic compared to the prototype HBc18-27 sequence, and they could not be recognized by CTL clones specific for the prototype peptide. While we do not know if the two patients were originally infected by these variant viruses or if the variants emerged subsequent to infection because of immune selection, the results are most consistent with the latter hypothesis. If this is correct, the data suggest that negative selection of mutant viral genomes might contribute to viral persistence in a subset of patients with chronic HBV infection who express a narrow repertoire of anti-HBV CTL responses.

scholarly journals Identification of Aquarius and Senataxin as Restriction Host Factors for Hepatitis B Virus Infection

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 2
Author(s):  
Christina Whitten-Bauer ◽  
Andoni Gómez-Moreno ◽  
Urtzi Garaigorta
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Core Protein ◽  
Sodium Taurocholate ◽  
Hbv Infection ◽  
Loss Of Function ◽  
Glycosylation Pattern ◽  
Hbv Cccdna ◽  
Cellular Factors ◽  
B Virus

Hepatitis B virus (HBV) represents an important human pathogen causing acute and chronic hepatitis. Over 240 million people are chronically infected, many of whom will die due to complications such as liver cirrhosis and hepatocellular carcinoma. Currently approved therapies are very effective in suppressing virus replication and viremia, but they are not curative, because they do not completely eliminate the nuclear episomal DNA form of HBV (cccDNA) that re-establishes infection upon interruption of therapy. Despite our understanding of many aspects of the HBV lifecycle, details of the HBV cccDNA biology remain poorly understood. Our group is pursuing a loss-of-function genetic screening approach, to identify cellular factors regulating HBV infection. A lentivirus-delivered short hairpin RNA (shRNA) library, composed of 384 shRNAs, was used to interrogate the function of 80 DNA damage repair pathway proteins in the establishment of HBV infection. The primary screening identified 10 cellular factors that regulate the HBV infection both positively or negatively. Two of those proteins, aquarius (AQR) and senataxin (SETX), were subsequently validated as factors restricting the HBV infection in independent experiments. Silencing of AQR and SETX led to an increased infection efficiency that was characterized by higher intracellular levels of HBV cccDNA, HBV mRNA, and core protein, and increased HBV e antigen (HBeAg) accumulation in the supernatants of infected cells. The expression level, glycosylation pattern, and localization of the HBV receptor, sodium taurocholate cotransporting polypeptide (NTCP), in AQR- and SETX-downregulated cells was equivalent to that of the control cells. Collectively, our results are compatible with AQR and SETX restricting early steps in the HBV lifecycle and downstream HBV entry, that affect the establishment of the HBV cccDNA pool. Experiments to unravel the function of these proteins in the context of HBV infection are currently underway.

Study on the relationship between clearance of HBeAg and subtypes of HBsAg in patients with chronic HBV infection.

Kanzo ◽  
1990 ◽  
Vol 31 (3) ◽  
pp. 353-354
Author(s):  
Shoichi HIGUCHI ◽  
Hironobu TAWARAYA ◽  
Tadashi KOBAYASHI ◽  
Toru MIYAJIMA ◽  
Hidenori HARA ◽  
...  
Keyword(s):  
Hbv Infection ◽  
Chronic Hbv Infection ◽  
Chronic Hbv ◽  
The Relationship

Development of Steatohepatitis and Fibrosis in Chronic HBV Infection Is Linked to Inflammatory Responses Mediated by IL-13 and CCL11

2019 ◽  
Author(s):  
Sui-Weng Wong ◽  
Yi-Wen Ting ◽  
Yean-Kong Yong ◽  
Hong-Yien Tan ◽  
Muttiah Barathan ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Hbv Infection ◽  
Chronic Hbv Infection ◽  
Chronic Hbv

scholarly journals Possible role of tocopherols in the modulation of host microRNA with potential antiviral activity in patients with hepatitis B virus-related persistent infection: a systematic review

2014 ◽  
Vol 112 (11) ◽  
pp. 1751-1768 ◽  
Author(s):  
S. Fiorino ◽  
L. Bacchi-Reggiani ◽  
S. Sabbatani ◽  
F. Grizzi ◽  
L. di Tommaso ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Antiviral Activity ◽  
Hbv Infection ◽  
Cochrane Library ◽  
Viral Pathogen ◽  
Increased Risk ◽  
B Virus ◽  
Chronic Hbv

Hepatitis B virus (HBV) infection represents a serious global health problem and persistent HBV infection is associated with an increased risk of cirrhosis, hepatocellular carcinoma and liver failure. Recently, the study of the role of microRNA (miRNA) in the pathogenesis of HBV has gained considerable interest as well as new treatments against this pathogen have been approved. A few studies have investigated the antiviral activity of vitamin E (VE) in chronic HBV carriers. Herein, we review the possible role of tocopherols in the modulation of host miRNA with potential anti-HBV activity. A systematic research of the scientific literature was performed by searching the MEDLINE, Cochrane Library and EMBASE databases. The keywords used were ‘HBV therapy’, ‘HBV treatment’, ‘VE antiviral effects’, ‘tocopherol antiviral activity’, ‘miRNA antiviral activity’ and ‘VE microRNA’. Reports describing the role of miRNA in the regulation of HBV life cycle,in vitroandin vivoavailable studies reporting the effects of VE on miRNA expression profiles and epigenetic networks, and clinical trials reporting the use of VE in patients with HBV-related chronic hepatitis were identified and examined. Based on the clinical results obtained in VE-treated chronic HBV carriers, we provide a reliable hypothesis for the possible role of this vitamin in the modulation of host miRNA profiles perturbed by this viral pathogen and in the regulation of some cellular miRNA with a suggested potential anti-HBV activity. This approach may contribute to the improvement of our understanding of pathogenetic mechanisms involved in HBV infection and increase the possibility of its management and treatment.

scholarly journals Hepatitis B Core-Related Antigen as Surrogate Biomarker of Intrahepatic Hepatitis B Virus Covalently-Closed-Circular DNA in Patients with Chronic Hepatitis B: A Meta-Analysis

Diagnostics ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 187
Author(s):  
Gian Paolo Caviglia ◽  
Angelo Armandi ◽  
Chiara Rosso ◽  
Davide Giuseppe Ribaldone ◽  
Rinaldo Pellicano ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hepatitis B Surface Antigen ◽  
Meta Analysis ◽  
Circular Dna ◽  
Non Invasive ◽  
Hbv Cccdna ◽  
B Virus ◽  
Chronic Hbv ◽  
Intrahepatic Hbv

Hepatitis B virus (HBV) covalently-closed-circular (ccc)DNA is the key molecule responsible for viral persistence within infected hepatocytes. The evaluation of HBV cccDNA is crucial for the management of patients with chronic HBV infection and for the personalization of treatment. However, the need for liver biopsy is the principal obstacle for the assessment of intrahepatic HBV cccDNA. In the last decade, several studies have investigated the performance of hepatitis B core-related antigen (HBcrAg) as a surrogate of HBV cccDNA amount in the liver. In this meta-analysis, we collected 14 studies (1271 patients) investigating the correlation between serum HBcrAg and intrahepatic HBV cccDNA. Serum HBcrAg showed a high correlation with intrahepatic HBV cccDNA (r = 0.641, 95% confidence interval (CI) 0.510–0.743, p < 0.001). In a head-to-head comparison, we observed that the performance of HBcrAg was significantly superior to that of hepatitis B surface antigen (r = 0.665 vs. r = 0.475, respectively, p < 0.001). Subgroup analysis showed that the correlation between HBcrAg and intrahepatic HBV cccDNA was high, both in hepatitis B e antigen-positive and -negative patients (r = 0.678, 95% CI 0.403–0.840, p < 0.001, and r = 0.578, 95% CI 0.344–0.744, p < 0.001, respectively). In conclusion, the measurement of serum HBcrAg qualifies as a reliable non-invasive surrogate for the assessment of an intrahepatic HBV cccDNA reservoir.

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