Hepatitis B virus basal core promoter mutations show lower replication fitness associated with cccDNA acetylation status

Koumbi, Lemonica; Pollicino, Teresa; Raimondo, Giovanni; Stampoulis, Dimitrios; Khakoo, Salim I.; Karayiannis, Peter

doi:10.1016/j.virusres.2016.04.022

Cited by 16 publications

(17 citation statements)

References 48 publications

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“…This leads to increased binding of cyclic AMP-responsive enhancer binding protein (CREB) binding protein (CBP) and enhanced histone-acetylation status, resulting in increased cccDNA transcription [25,28]. The responsible domain is found to be the CTD, while NTD does not affect HBV replication [30]. Specifically, the arginine clusters III and IV on CTD are involved in HBV transcription [31].…”

Section: Intracellular Cccdna Amplification and Regulationmentioning

confidence: 99%

Hepatitis B core protein as a therapeutic target

Mak

Wong

Seto

et al. 2017

Expert Opinion on Therapeutic Targets

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Chronic hepatitis B virus (HBV) infection is difficult to cure, due to the presence of covalently-closed-circular DNA and virus-mediated blunting of host immune response. Existing therapies with nucleos(t)ide analogue or pegylated-interferon are not sufficient to achieve a high rate of HBV surface antigen seroclearance, a more desirable treatment outcome. Novel therapeutic agents targeting alternative viral replication steps are being developed. In this review, we will discuss the hepatitis B core antigen (HBcAg) as a therapeutic target. Areas covered: The basic structure and fundamental functions of HBcAg including nucleocapsid assembly, pre-genomic RNA encapsidation, reverse transcription, virion formation, cccDNA amplification, immune response regulation, and HBx protein interaction will be reviewed. Most of these are identified as therapeutic targets and tested in in vitro and in vivo studies, although clinical trials are scanty. Among the different components, the core protein allosteric modulators (CpAM) have been most widely investigated and appear promising in clinical trials. Expert opinion: The multiple and essential functions of HBcAg for HBV life cycle are important and attractive targets for HBV therapeutic interventions. Controlled trials involving CpAM are awaited. Apart from CpAM, drugs directed against different functions of HBcAg may be further explored to maximize the chance of cure.

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Section: Intracellular Cccdna Amplification and Regulationmentioning

confidence: 99%

Hepatitis B core protein as a therapeutic target

Mak

Wong

Seto

et al. 2017

Expert Opinion on Therapeutic Targets

View full text Add to dashboard Cite

show abstract

“…Characteristically, HBV mutations have different effects on viral replication and disease progression, particularly in hepatocyte malignant transformation. For example, the A1762T/G1764A and G1896A mutations were reported to be associated with the severity of hepatitis and the development of HCC, and resulted in significantly lower HBV transcription capacity, while core L60V was reported to be relevant to significantly higher viral replication . In the previous study, we found a high frequency of T1719G mutation in tumour tissues, and the T1719G mutation was an independent risk factor for prognosis prediction.…”

Section: Introductionmentioning

confidence: 70%

HBV T1719G mutation reduced HBV replication through mutant Enh II and HBx protein in vitro

Jiao

Shen

Ning

et al. 2019

Journal of Viral Hepatitis

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Summary It was repeatedly reported that the hepatitis B virus (HBV) T1719G mutation was very common and related to progression and malignancy of liver disease. However, its effect on viral replication efficiency remains unclear. In this study, we aimed to evaluate the function and mechanisms of the T1719G mutation on viral replication capacity. Wild‐type and T1719G mutation‐bearing HBV1.2× plasmids were transfected into Huh7 and HepG2 cells, respectively, and HBV total RNA, 3.5 kb RNA and supernatant HBV DNA were assessed using real‐time PCR, hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) levels were measured by time‐resolved fluoroimmunoassay. In order to assess Enh II activity and the binding capacity of HNF3β to Enh II sequence, dual‐luciferase assay and Chromatin immunoprecipitation (ChIP)‐PCR were employed, respectively. Simultaneously, the HBx or HBx‐mut (T1719G) plasmid was co‐transfected to evaluate the effect of HBx on viral replication. Our results showed that the T1719G mutation impaired viral replication efficacy compared with the wild type both by reducing Enh II activity and binding capacity of HNF3β with Enh II. And such reduction caused by T1719G mutation could be rescued by HBx protein. Our results show that the T1719G mutation decreases HBV viral replication capacity possibly by mutant HBx protein and altered Enh II activity.

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“…The appearance of the BCP or Pre-C mutations, which reduce or abolish HBeAg production[9, 20], heralds the initiation of the seroconversion phase from HBeAg to anti-HBeAg positivity in clinical[21]. The remove of the HBeAg often lead to the awakening of the immune response[22].…”

Section: Discussionmentioning

confidence: 99%

The effect of basal core promoter and pre-core mutations on HBV replication and persistence in mice

Chen

Zeng

et al. 2020

Preprint

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The appearance of the BCP or Pre-C mutations, which reduce or abolish HBeAg production, could increase HBV replication. The remove of the HBeAg often lead to a vigorous immune response, which has an important role in HBV related fulminant outcome. In this study, BCP mutations and Pre-C mutations were separately introduced by site-directed mutagenesis in the same genetic background of an HBV infectious clone, to determine the effect of these mutations per se on replication. BCP and Pre-C mutations increased HBV replication both in vitro and in vivo . HBV could persist in mice injected with wild type HBV infectious clone for about 7 weeks. However, HBV could persist about 5 weeks in mice injected with BCP HBV infectious clone, and 3 weeks only in mice injected with Pre-C HBV infectious clone. HBV related CD8+ CTL response in BCP HBV infectious clone injected mice only slightly increased, but significantly increased in Pre-C HBV infectious clone injected mice compared with that in wild type HBV infectious clone injected mice. The population of Tregs significantly increased in liver but not in spleen of mice injected with Pre-C HBV infectious clone. In summary, we demonstrate that HBeAg plays an important role in suppressing the CTL response, which is related with increasing the frequency of Tregs in mouse. Lack of HBeAg expression leads to the partial loss of immune tolerance.

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Hepatitis B virus basal core promoter mutations show lower replication fitness associated with cccDNA acetylation status

Cited by 16 publications

References 48 publications

Hepatitis B core protein as a therapeutic target

Hepatitis B core protein as a therapeutic target

HBV T1719G mutation reduced HBV replication through mutant Enh II and HBx protein in vitro

The effect of basal core promoter and pre-core mutations on HBV replication and persistence in mice

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