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  1 , Marie-Anne Meier  2 , Sylvia Ketterer  1 , Xueya Wang  1 , Stefan Wieland  3 , Markus Hermann Heim  4
Affiliations
Affiliations

    1
    Department of Biomedicine, University Hospital Basel, University of Basel, Basel CH-4031, Switzerland.
    2
    Department of Biomedicine, University Hospital Basel, University of Basel, Basel CH-4031, Switzerland; Division of Gastroenterology and Hepatology, University Center for Gastrointestinal and Liver Diseases, Basel CH-4002, Switzerland.
    3
    Department of Biomedicine, University Hospital Basel, University of Basel, Basel CH-4031, Switzerland. Electronic address: [email protected].
    4
    Department of Biomedicine, University Hospital Basel, University of Basel, Basel CH-4031, Switzerland; Division of Gastroenterology and Hepatology, University Center for Gastrointestinal and Liver Diseases, Basel CH-4002, Switzerland. Electronic address: [email protected].

    PMID: 33188905 DOI: 10.1016/j.jhep.2020.11.003

Abstract

Background: 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 what 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 ENCHB. Furthermore, a subgroup of ENCHB patients is characterized by reduced replication efficiency downstream of pgRNA.

Conclusions: Reduction of HBV serum viral load during transition to ENCI seems to be primarily the results of a strong inhibition of cccDNA transcriptional activity which can be maintained in the absence of liver disease.

Keywords: Liver; biopsy; replication; viral control.

Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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
Aleksei Suslov 1，Marie-Anne Meier 2，Sylvia Ketterer 1，王雪雅1，Stefan Wieland 3，Markus Hermann Heim 4
隶属关系
隶属关系

    1个
    巴塞尔大学巴塞尔大学医院生物医学系，瑞士巴塞尔CH-4031。
    2
    瑞士巴塞尔大学巴塞尔大学医院生物医学系，瑞士巴塞尔CH-4031；瑞士巴塞尔CH-4002大学胃肠病和肝病中心胃肠病学和肝病学科。
    3
    瑞士巴塞尔大学巴塞尔大学医院生物医学系，瑞士CH-4031。电子地址：[email protected]。
    4
    瑞士巴塞尔大学巴塞尔大学医院生物医学系，瑞士巴塞尔CH-4031；瑞士巴塞尔CH-4002大学胃肠病和肝病中心胃肠病学和肝病学科。电子地址：[email protected]。

    PMID：33188905 DOI：10.1016 / j.jhep.2020.11.003

抽象

背景：在慢性乙型肝炎（CHB）的自然病史中，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68例活检中不同阶段患者的cccDNA，基因组前RNA（pgRNA），总HBV RNA和DNA复制中间体进行了定量CHB。

结果：HBeAg血清转化与cccDNA数量减少以及转录活性有关。 cccDNA的沉默在ENCI中尤为明显，其中每个cccDNA的pgRNA比ENCHB低约46倍。此外，ENCHB患者亚组的特征是pgRNA下游的复制效率降低。

结论：过渡到ENCI期间HBV血清病毒载量的减少似乎主要是强烈抑制cccDNA转录活性的结果，这种表达可以在没有肝脏疾病的情况下得以维持。

关键词：肝;活检复制；病毒控制。

版权所有©2020欧洲肝脏研究协会。由Elsevier B.V.发布。保留所有权利。