Hepatitis B Virus Capsid: The Core in Productive Entry and Covalently Closed Circular DNA Formation

Abstract

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.

Immunoinformatics and Evaluation of Peptide Vaccines Derived from Global Hepatitis B Viral HBx and HBc Proteins Critical for Covalently Closed Circular DNA Integrity

“…Using conserved epitopes predicted from global consensus sequences against NS3-4A could offer broader protection against multiple isotypes of the Hepatitis C virus [49]. Given the significant role of viral HBx and HBc proteins in association with cccDNA in promoting HBV replication, achieving a functional HBV cure remains a formidable challenge [50][51][52][53][54][55][56][57][58]. This study paves the way for designing innovative anti-HBV vaccines and therapeutics.…”

Highlights from the 2023 International Meeting on the Molecular Biology of Hepatitis B virus

“…Wang et al (in collaboration with Hu lab, The Pennsylvania State University College of Medicine) studied empty hepatitis B virions purified from patient serum by single-particle cryo-EM, providing the first visualisation of the surface protein-capsid interaction, and showed that the lipid components of the virion envelope layer were not organised in a traditional bilayer. Noting the critical role for nucleocapsids in the viral replication cycle, ongoing efforts to resolve high-resolution structures of hepatitis B capsids and virions could help develop new antiviral strategies [23].…”

Mcl-1 Protein and Viral Infections: A Narrative Review

“…Its genome is covered by a capsid composed of 240 copies of the HBV core protein. The lipid envelope encircles the capsid and contains three HBV surface antigens (HBsAg)-large (L), middle (M), and small (S) [17]. It is estimated that 250 million people live with chronic HBV infection [18].…”