Hepatitis B Virus Core Protein Is Not Required for Covalently Closed Circular DNA Transcriptional Regulation
Hepatitis B Virus Core Protein Is Not Required for Covalently Closed Circular DNA Transcriptional Regulation
复制标题
DOI：
10.1128/jvi.01362-22
复制
发表时间：
2022-10
影响因子：
5.4
通讯作者：
Youquan Zhong;Chuanjian Wu;Zaichao Xu;Yan Teng;Li Zhao;Kaitao Zhao;Jingjing Wang;Wen Wang;Qiong Zhan;Chengliang Zhu;Xinwen Chen;Kaiwei Liang;Xiaoming Cheng;Yuchen Xia
中科院分区：
文献类型：
--
作者：
Youquan Zhong;Chuanjian Wu;Zaichao Xu;Yan Teng;Li Zhao;Kaitao Zhao;Jingjing Wang;Wen Wang;Qiong Zhan;Chengliang Zhu;Xinwen Chen;Kaiwei Liang;Xiaoming Cheng;Yuchen Xia
B型肝炎病毒（HBV）核心蛋白（HBc）已成为一个有前途的抗病毒靶点。然而，HBc是否可以调节HBV共价闭合环状DNA（cccDNA）的转录仍然难以捉摸。这项研究表明，HBc对cccDNA的表观遗传调控没有影响，它不参与cccDNA的转录。考虑到HBc对cccDNA转录的抑制作用，需要新的cccDNA靶向治疗剂来治愈HBV。摘要B型肝炎病毒（HBV）感染是世界范围内的主要健康负担，目前尚无治愈方法。HBV共价闭合环状DNA（cccDNA）的持续存在是抗病毒治疗的主要障碍。HBV核心蛋白（HBc）在病毒生命周期的关键步骤中发挥重要作用，已成为一个有前途的抗病毒靶点。然而，HBc是否可以调节HBV cccDNA转录仍存在争议。在这项研究中，使用了不同的方法来解决这个问题。在合成的HBV cccDNA和HBVcircle转染试验中，缺乏HBc对肝癌细胞系和原代人肝细胞中HBV RNA的转录以及HBV表面抗原（HBsAg）的产生没有影响。HBc的重建没有改变cccDNA衍生的HBV标志物的表达。从携带cccDNA的体内小鼠模型获得了类似的结果。染色质免疫沉淀（ChIP）或ChIP测序分析显示HBc缺陷cccDNA染色质的转录调控与野生型cccDNA相似。此外，用衣壳组装调节剂（CAMs）处理显著减少细胞外HBV DNA，但不能改变病毒RNA和HBsAg。我们的研究结果表明，HBc既不影响组蛋白修饰和转录因子结合的cccDNA，也不直接影响cccDNA转录。尽管CAM可以减少HBc与cccDNA的结合，但它们不抑制cccDNA的转录活性。因此，靶向衣壳或HBc的治疗剂不应预期足以降低cccDNA转录。重要性B型肝炎病毒（HBV）核心蛋白（HBc）已成为一个有前途的抗病毒靶点。然而，HBc是否可以调节HBV共价闭合环状DNA（cccDNA）的转录仍然难以捉摸。这项研究表明，HBc对cccDNA的表观遗传调控没有影响，它不参与cccDNA的转录。考虑到HBc对cccDNA转录的抑制作用，需要新的cccDNA靶向治疗剂来治愈HBV。
Hepatitis B virus (HBV) core protein (HBc) has emerged as a promising antiviral target. However, whether HBc can regulate HBV covalently closed circular DNA (cccDNA) transcription remains elusive. This study illustrated that HBc has no effect on epigenetic regulation of cccDNA, and it does not participate in cccDNA transcription. Given that HBc is dispensable for cccDNA transcription, novel cccDNA-targeting therapeutics are needed for an HBV cure. ABSTRACT Hepatitis B virus (HBV) infection is a major health burden worldwide, and currently there is no cure. The persistence of HBV covalently closed circular DNA (cccDNA) is the major obstacle for antiviral trement. HBV core protein (HBc) has emerged as a promising antiviral target, as it plays important roles in critical steps of the viral life cycle. However, whether HBc could regulate HBV cccDNA transcription remains under debate. In this study, different approaches were used to address this question. In synthesized HBV cccDNA and HBVcircle transfection assays, lack of HBc showed no effect on transcription of HBV RNA as well as HBV surface antigen (HBsAg) production in a hepatoma cell line and primary human hepatocytes. Reconstitution of HBc did not alter the expression of cccDNA-derived HBV markers. Similar results were obtained from an in vivo mouse model harboring cccDNA. Chromatin immunoprecipitation (ChIP) or ChIP sequencing assays revealed transcription regulation of HBc-deficient cccDNA chromatin similar to that of wild-type cccDNA. Furthermore, treatment with capsid assembly modulators (CAMs) dramatically reduced extracellular HBV DNA but could not alter viral RNA and HBsAg. Our results demonstrate that HBc neither affects histone modifications and transcription factor binding of cccDNA nor directly influences cccDNA transcription. Although CAMs could reduce HBc binding to cccDNA, they do not suppress cccDNA transcriptional activity. Thus, therapeutics targeting capsid or HBc should not be expected to sufficiently reduce cccDNA transcription. IMPORTANCE Hepatitis B virus (HBV) core protein (HBc) has emerged as a promising antiviral target. However, whether HBc can regulate HBV covalently closed circular DNA (cccDNA) transcription remains elusive. This study illustrated that HBc has no effect on epigenetic regulation of cccDNA, and it does not participate in cccDNA transcription. Given that HBc is dispensable for cccDNA transcription, novel cccDNA-targeting therapeutics are needed for an HBV cure.