1. Academic Validation
  2. 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

  • J Virol. 2022 Oct 13;e0136222. doi: 10.1128/jvi.01362-22.
Youquan Zhong # 1 2 Chuanjian Wu # 1 Zaichao Xu 1 Yan Teng 1 Li Zhao 1 Kaitao Zhao 1 Jingjing Wang 1 Wen Wang 3 Qiong Zhan 1 Chengliang Zhu 4 Xinwen Chen 5 Kaiwei Liang 3 Xiaoming Cheng 1 6 7 Yuchen Xia 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan Universitygrid.49470.3e, Wuhan, China.
  • 2 Department of Laboratory Medicine, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.
  • 3 Department of Pathophysiology, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan Universitygrid.49470.3e, Wuhan, China.
  • 4 Department of Clinical Laboratory, Renmin Hospital of Wuhan Universitygrid.49470.3e, Wuhan, China.
  • 5 State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
  • 6 Wuhan Universitygrid.49470.3e Center for Pathology and Molecular Diagnostics, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 7 Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China.
  • # Contributed equally.
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.

Keywords

capsid inhibitor; cccDNA; core protein; hepatitis B virus; transcriptional regulation.

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