Hepatitis B Virus Capsid: The Core in Productive Entry and Covalently Closed Circular DNA Formation
Hepatitis B virus (HBV) relies on the core protein (HBc) to establish productive infection, as defined by the formation of the covalently closed circularized DNA (cccDNA), as well as to carry out almost every step of the lifecycle following cccDNA formation. Multiple copies of HBc form an icosahedra...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-02-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/15/3/642 |
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| author | Megan A. Mendenhall Xupeng Hong Jianming Hu |
| author_facet | Megan A. Mendenhall Xupeng Hong Jianming Hu |
| author_sort | Megan A. Mendenhall |
| collection | DOAJ |
| description | Hepatitis B virus (HBV) relies on the core protein (HBc) to establish productive infection, as defined by the formation of the covalently closed circularized DNA (cccDNA), as well as to carry out almost every step of the lifecycle following cccDNA formation. Multiple copies of HBc form an icosahedral capsid shell that encapsidates the viral pregenomic RNA (pgRNA) and facilitates the reverse transcription of pgRNA to a relaxed circular DNA (rcDNA) within the capsid. During infection, the complete HBV virion, which contains an outer envelope layer in addition to the internal nucleocapsid containing rcDNA, enters human hepatocytes via endocytosis and traffics through the endosomal compartments and the cytosol to deliver its rcDNA to the nucleus to produce cccDNA. In addition, progeny rcDNA, newly formed in cytoplasmic nucleocapsids, is also delivered to the nucleus in the same cell to form more cccDNA in a process called intracellular cccDNA amplification or recycling. Here, we focus on recent evidence demonstrating differential effects of HBc in affecting cccDNA formation during de novo infection vs. recycling, obtained using HBc mutations and small molecule inhibitors. These results implicate a critical role of HBc in determining HBV trafficking during infection, as well as in nucleocapsid disassembly (uncoating) to release rcDNA, events essential for cccDNA formation. HBc likely functions in these processes via interactions with host factors, which contributes critically to HBV host tropism. A better understanding of the roles of HBc in HBV entry, cccDNA formation, and host species tropism should accelerate ongoing efforts to target HBc and cccDNA for the development of an HBV cure and facilitate the establishment of convenient animal models for both basic research and drug development. |
| first_indexed | 2024-03-11T05:46:28Z |
| format | Article |
| id | doaj.art-0fb410cf110648968bee4ab369d764d2 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-11T05:46:28Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-0fb410cf110648968bee4ab369d764d22023-11-17T14:22:18ZengMDPI AGViruses1999-49152023-02-0115364210.3390/v15030642Hepatitis B Virus Capsid: The Core in Productive Entry and Covalently Closed Circular DNA FormationMegan A. Mendenhall0Xupeng Hong1Jianming Hu2Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USADepartment of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USADepartment of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USAHepatitis B virus (HBV) relies on the core protein (HBc) to establish productive infection, as defined by the formation of the covalently closed circularized DNA (cccDNA), as well as to carry out almost every step of the lifecycle following cccDNA formation. Multiple copies of HBc form an icosahedral capsid shell that encapsidates the viral pregenomic RNA (pgRNA) and facilitates the reverse transcription of pgRNA to a relaxed circular DNA (rcDNA) within the capsid. During infection, the complete HBV virion, which contains an outer envelope layer in addition to the internal nucleocapsid containing rcDNA, enters human hepatocytes via endocytosis and traffics through the endosomal compartments and the cytosol to deliver its rcDNA to the nucleus to produce cccDNA. In addition, progeny rcDNA, newly formed in cytoplasmic nucleocapsids, is also delivered to the nucleus in the same cell to form more cccDNA in a process called intracellular cccDNA amplification or recycling. Here, we focus on recent evidence demonstrating differential effects of HBc in affecting cccDNA formation during de novo infection vs. recycling, obtained using HBc mutations and small molecule inhibitors. These results implicate a critical role of HBc in determining HBV trafficking during infection, as well as in nucleocapsid disassembly (uncoating) to release rcDNA, events essential for cccDNA formation. HBc likely functions in these processes via interactions with host factors, which contributes critically to HBV host tropism. A better understanding of the roles of HBc in HBV entry, cccDNA formation, and host species tropism should accelerate ongoing efforts to target HBc and cccDNA for the development of an HBV cure and facilitate the establishment of convenient animal models for both basic research and drug development.https://www.mdpi.com/1999-4915/15/3/642hepatitis B viruscccDNAcapsidHBcinfectionhost factors |
| spellingShingle | Megan A. Mendenhall Xupeng Hong Jianming Hu Hepatitis B Virus Capsid: The Core in Productive Entry and Covalently Closed Circular DNA Formation Viruses hepatitis B virus cccDNA capsid HBc infection host factors |
| title | Hepatitis B Virus Capsid: The Core in Productive Entry and Covalently Closed Circular DNA Formation |
| title_full | Hepatitis B Virus Capsid: The Core in Productive Entry and Covalently Closed Circular DNA Formation |
| title_fullStr | Hepatitis B Virus Capsid: The Core in Productive Entry and Covalently Closed Circular DNA Formation |
| title_full_unstemmed | Hepatitis B Virus Capsid: The Core in Productive Entry and Covalently Closed Circular DNA Formation |
| title_short | Hepatitis B Virus Capsid: The Core in Productive Entry and Covalently Closed Circular DNA Formation |
| title_sort | hepatitis b virus capsid the core in productive entry and covalently closed circular dna formation |
| topic | hepatitis B virus cccDNA capsid HBc infection host factors |
| url | https://www.mdpi.com/1999-4915/15/3/642 |
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