向HBeAg阴性慢性乙型肝炎病毒感染的转变与cccDNA转录活性降低有关。
Transition to HBeAg-negative chronic hepatitis B virus infection is associated with reduced cccDNA transcriptional activity.
作者信息
Suslov Aleksei, Meier Marie-Anne, Ketterer Sylvia, Wang Xueya, Wieland Stefan, Heim Markus Hermann
机构信息
Department of Biomedicine, University Hospital Basel, University of Basel, Basel, CH-4031, Switzerland.
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.
出版信息
J Hepatol. 2021 Apr;74(4):794-800. doi: 10.1016/j.jhep.2020.11.003. Epub 2020 Nov 11.
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.
背景与目的
慢性乙型肝炎（CHB）自然病程中的HBeAg血清学转换与血清HBV DNA水平的显著下降以及肝内共价闭合环状DNA（cccDNA）含量的减少有关。向HBeAg阴性慢性感染（ENCI）的转变尤其值得关注。ENCI以前被称为非活动性携带者状态，其特征是病毒血症极低或呈阴性且无肝病。导致向ENCI转变以及ENCI中病毒复制控制的分子机制仍知之甚少。
方法
为了确定在向ENCI转变过程中病毒生命周期的哪些步骤受到控制，我们对68例处于CHB不同阶段患者的活检组织中的cccDNA、前基因组RNA（pgRNA）、总HBV RNA和DNA复制中间体进行了定量分析。
结果
HBeAg血清学转换与cccDNA数量以及转录活性的降低有关。cccDNA的沉默在ENCI中尤为明显，与HBeAg阴性CHB相比，ENCI中每个cccDNA的pgRNA减少了约46倍。此外，一部分HBeAg阴性CHB患者的特征是pgRNA下游的复制效率降低。
结论
向ENCI转变过程中血清病毒载量的降低似乎主要是由于cccDNA转录活性受到强烈抑制，而这种抑制在无肝病的情况下仍可维持。
简要概述
在慢性乙型肝炎病毒感染的自然病程中，免疫反应可控制病毒复制。对慢性乙型肝炎不同阶段患者肝活检中的病毒DNA和RNA进行定量分析，使我们能够确定从活动性疾病转变为非活动性疾病过程中受影响的病毒生命周期步骤。针对这些步骤进行治疗可能会诱导病毒转录的持续抑制。
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