Role of HBx in hepatitis B virus persistence and its therapeutic implications

Abstract

Chronic hepatitis B virus infection is a significant risk factor for cirrhosis and hepatocellular carcinoma. The HBx protein is required for virus replication, but the lack of robust infection models has hindered our understanding of HBx functions that could be targeted for antiviral purposes. We briefly review three properties of HBx: its binding to DDB1 and its regulation of cell survival and metabolism, to illustrate how a single viral protein can have multiple effects in a cell. We propose that different functions of HBx are needed, depending on the changing hepatocyte environment encountered during a chronic virus infection, and that these functions might serve as novel therapeutic targets for inhibiting hepatitis B virus replication and the development of associated diseases.

Figure 1

HBV lifecycle. Virus particles containing partially double-stranded (ds) DNA (∼dsDNA) genomes enter the cell via the NTCP receptor. Following uncoating of surface antigen (small blue circles), the core particles (hexagons) deliver the genome to the nucleus. The ∼dsDNA is repaired by host factors and converted into covalently closed circular (ccc)DNA. The cccDNA serves as the template for HBx-mediated viral transcription. The viral mRNAs (shown in the nucleus) are transported to the cytoplasm for translation. The 3.5-kb pregenomic RNA and a copy of the viral polymerase (small black circles) is encapsidated and reverse transcribed (RT) into the negative-strand DNA, which is then copied into positive-strand DNA. Viral cores move through the endoplasmic reticulum and Golgi, where they acquire surface antigen (envelope) and bud from the cell. Cytoplasmic-core particles may alternatively recycle back to the nucleus.

Figure 2

Four stages of a chronic HBV infection. Chronic HBV infection typically proceeds through four stages, .as described in the text. We propose that HBx activities may differ depending on the cellular factors present during the different stages of a chronic infection.

Figure 3

HBx and DDB1. DDB1 (orange) is an adaptor protein of the Cullin 4A-DDB1 E3 Ligase (CRL4) and acts by recruiting DCAF-receptor proteins (R) that bind substrates (S) that are ubiquitinated (Ub) and degraded to regulate downstream pathways such as DNA synthesis, damaged-DNA repair, the cell cycle, and innate immunity. HBx is a viral DCAF and binds DDB1 as a required step in virus replication. HBx-DDB1 may recruit new substrates (S′) to the CRL4 or may alter downstream pathways regulated by CRL4. Other key proteins of the complex are the RING protein (Roc) that binds to the E2 enzyme.