The diverse functions of the hepatitis B core/capsid protein (HBc) in the viral life cycle: Implications for the development of HBc-targeting antivirals

Abstract

Virally encoded proteins have evolved to perform multiple functions, and the core protein (HBc) of the hepatitis B virus (HBV) is a perfect example. While HBc is the structural component of the viral nucleocapsid, additional novel functions for the nucleus-localized HBc have recently been described. These results extend for HBc, beyond its structural role, a regulatory function in the viral life cycle and potentially a role in pathogenesis. In this article, we review the diverse roles of HBc in HBV replication and pathogenesis, emphasizing how the unique structure of this protein is key to its various functions. We focus in particular on recent advances in understanding the significance of HBc phosphorylations, its interaction with host proteins and the role of HBc in regulating the transcription of host genes. We also briefly allude to the emerging niche for new direct-acting antivirals targeting HBc, known as Core (protein) Allosteric Modulators (CAMs).

Keywords: CAMs; Core allosteric modulators; HBV; HBV core antigen; HBc; HBc phosphorylations; HBc structure; Hepatitis B virus; PLK1.

Fig. 1

Stages of the HBV life cycle regulated by HBc. 1) HBc regulates transport and nuclear release of the viral genome (Blondot et al., 2016). 2) HBc associates with cccDNA (Guo et al., 2011). 3) HBc modulates host gene expression (Xie et al., 2017). 4) HBc is required for pgRNA encapsidation (Nassal, 1992). 5) HBc is required for reverse transcription (Lewellyn and Loeb, 2011), and 6) persistence of cccDNA involves recycling of nucleocapsids into the nucleus (Nassal, 2015).

Fig. 2

Arginine-rich motifs of different viral proteins exhibit an abundance of arginine residues within short 10–20 residues. The arginine-rich domain of HBc has distinct nuclear localization (NLS) and cytoplasmic retention signals (CRS) (Li et al., 2010).

Fig. 3

HBc C-terminal domain (CTD) is a phosphorylation substrate for CDK2 (SP sites at positions 155, 162 and 170) and PLK1 (phosphorylation sites at positions 168, 176 and 178), as shown by Ludgate et al. (2012) and Diab et al. (2017), respectively.

Fig. 4

Top view of an HBc hexamer in complex with CAM sulfamoylbenzamide SBA_R01, PDB: 5T2P (Left) and CAM heteroaryldihydropyrimidine HAP_R01 PDB: 5WRE (Zhou et al., 2017) (Right).