向HBeAg阴性慢性乙型肝炎病毒感染的过渡与cccDNA转录活性降低

StephenW

Transition to HBeAg-negative chronic hepatitis B virus infection is associated with reduced cccDNA transcriptional activity

    Aleksei Suslov
    Marie-Anne Meier
    Sylvia Ketterer
    Xueya Wang
    Stefan Wieland ‡
    Markus Hermann Heim ‡
    Show footnotes

Open AccessPublished:November 11, 2020DOI:https://doi.org/10.1016/j.jhep.2020.11.003
Highlights

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    A unique set of liver biopsies from patients with chronic hepatitis B was studied.
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    Quantification of viral DNA and RNA revealed disease stage-specific virological profiles.
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    HBeAg-negative chronic infection is associated with reduced cccDNA transcription.
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    Inhibition of replication downstream of pgRNA found in a subgroup of patients with HBeAg-negative chronic hepatitis and low viral load.

Background & Aims
HBeAg seroconversion during the natural history of chronic hepatitis B (CHB) is associated with a strong drop in serum HBV DNA levels and a reduction of intrahepatic covalently closed circular DNA (cccDNA) content. Of particular interest is the transition to HBeAg-negative chronic infection (ENCI). ENCI, previously known as inactive carrier state, is characterized by very low or negative viremia and the absence of liver disease. The molecular mechanisms responsible for the transition to ENCI and for the control of viral replication in ENCI are still poorly understood.
Methods
To identify which step(s) in the viral life cycle are controlled during the transition to ENCI, we quantified cccDNA, pre-genomic RNA (pgRNA), total HBV RNA and DNA replicative intermediates in 68 biopsies from patients in different phases of CHB.
Results
HBeAg seroconversion is associated with a reduction of cccDNA amounts as well as transcriptional activity. Silencing of cccDNA is particularly pronounced in ENCI, where there was ~46 times less pgRNA per cccDNA compared to HBeAg-negative CHB. Furthermore, a subgroup of patients with HBeAg-negative CHB can be characterized by reduced replication efficiency downstream of pgRNA.
Conclusions
The reduction in serum viral load during the transition to ENCI seems to primarily result from strong inhibition of the transcriptional activity of cccDNA which can be maintained in the absence of liver disease.
Lay summary
During the natural course of chronic hepatitis B virus infections, the immune response can gain control of viral replication. Quantification of viral DNA and RNA in liver biopsies of patients in different stages of chronic hepatitis B allowed us to identify the steps in the viral life cycle that are affected during the transition from active to inactive disease. Therapeutic targeting of these steps might induce sustained inhibition of viral transcription.

StephenW

向HBeAg阴性慢性乙型肝炎病毒感染的过渡与cccDNA转录活性降低有关

    亚历山大·苏斯洛夫（Aleksei Suslov）
    玛丽·安妮·迈耶（Marie-Anne Meier）
    西尔维亚·凯特勒（Sylvia Ketterer）
    王雪雅
    斯蒂芬·威兰德（Stefan Wieland）‡
    马库斯·赫尔曼·海姆（Markus Hermann Heim）
    显示脚注

开放获取发布时间：2020年11月11日DOI：https：//doi.org/10.1016/j.jhep.2020.11.003
强调

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    研究了一组来自慢性乙型肝炎患者的独特肝活检。
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    病毒DNA和RNA的定量显示疾病阶段特定的病毒学概况。
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    HBeAg阴性慢性感染与cccDNA转录减少有关。
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    在HBeAg阴性慢性肝炎和低病毒载量患者亚组中发现了pgRNA下游复制的抑制作用。

背景与目标
在慢性乙型肝炎（CHB）的自然病程中，HBeAg血清转换与血清HBV DNA水平的大幅下降和肝内共价闭合环状DNA（cccDNA）含量的降低有关。特别令人感兴趣的是向HBeAg阴性慢性感染（ENCI）的过渡。 ENCI，以前称为无活性载体状态，其特征是病毒血症非常低或为阴性，并且没有肝脏疾病。对向ENCI过渡和控制ENCI中病毒复制的分子机制仍知之甚少。
方法
为了确定在向ENCI过渡期间病毒生命周期中的哪些步骤受到控制，我们对来自CHB不同阶段患者的68例活检样本中的cccDNA，前基因组RNA（pgRNA），总HBV RNA和DNA复制中间体进行了定量。
结果
HBeAg血清转化与cccDNA数量的减少以及转录活性有关。 cccDNA的沉默在ENCI中尤其明显，与HBeAg阴性CHB相比，每个cccDNA的pgRNA少46倍。此外，HBeAg阴性CHB患者的一个亚组的特征是pgRNA下游的复制效率降低。
结论
过渡到ENCI期间血清病毒载量的降低似乎主要是由于cccDNA转录活性的强烈抑制所致，而cccDNA的转录活性可以在没有肝脏疾病的情况下维持。
放置摘要
在慢性乙型肝炎病毒感染的自然过程中，免疫反应可以控制病毒复制。对慢性乙型肝炎不同阶段患者肝活检中病毒DNA和RNA的定量分析，使我们能够确定病毒生命周期中从活动性疾病过渡到非活动性疾病的各个步骤。这些步骤的治疗靶向可能会诱导病毒转录的持续抑制。

StephenW

https://www.journal-of-hepatolog ... 20)33753-3/fulltext