Cell-Free Hepatitis B Virus Capsid Assembly Dependent on the Core Protein C-Terminal Domain and Regulated by Phosphorylation.

Unlabelled: Multiple subunits of the hepatitis B virus (HBV) core protein (HBc) assemble into an icosahedral capsid that packages the viral pregenomic RNA (pgRNA). The N-terminal domain (NTD) of HBc is sufficient for capsid assembly, in the absence of pgRNA or any other viral or host factors, under conditions of high HBc and/or salt concentrations. The C-terminal domain (CTD) is deemed dispensable for capsid assembly although it is essential for pgRNA packaging.

Regulation of multiple stages of hepadnavirus replication by the carboxyl-terminal domain of viral core protein in trans.

Unlabelled: Mutational analyses have indicated that the carboxyl-terminal domain (CTD) of hepadnavirus core protein and its state of phosphorylation are critical for multiple steps in viral replication. Also, CTD interacts with host proteins in a phosphorylation state-dependent manner. To ascertain the role of CTD in viral replication without perturbing its sequence and the role of CTD-host interactions, CTD of the human hepatitis B virus (HBV) or duck hepatitis B virus (DHBV) core protein, either the wild type (WT) or with alanine or glutamic acid/aspartic acid substitutions at the phosphorylation sites, was expressed in cells replicating DHBV with the WT core protein.

Maturation-associated destabilization of hepatitis B virus nucleocapsid.

The mature nucleocapsid (NC) of hepatitis B virus containing the relaxed circular (RC) DNA genome can be secreted extracellularly as virions after envelopment with the viral surface proteins or, alternatively, can be disassembled to release RC DNA (i.e., uncoating) into the host cell nucleus to form the covalently closed circular (CCC) DNA, which sustains viral replication and persistence.

Cyclin-dependent kinase 2 phosphorylates s/t-p sites in the hepadnavirus core protein C-terminal domain and is incorporated into viral capsids.

Phosphorylation of the hepadnavirus core protein C-terminal domain (CTD) is important for viral RNA packaging, reverse transcription, and subcellular localization. Hepadnavirus capsids also package a cellular kinase. The identity of the host kinase that phosphorylates the core CTD or gets packaged remains to be resolved.

Phosphorylation state-dependent interactions of hepadnavirus core protein with host factors.

Dynamic phosphorylation and dephosphorylation of the hepadnavirus core protein C-terminal domain (CTD) are required for multiple steps of the viral life cycle. It remains unknown how the CTD phosphorylation state may modulate core protein functions but phosphorylation state-dependent viral or host interactions may play a role. In an attempt to identify host factors that may interact differentially with the core protein depending on its CTD phosphorylation state, pulldown assays were performed using the CTD of the duck hepatitis B virus (DHBV) and human hepatitis B virus (HBV) core protein, either with wild type (WT) sequences or with alanine or aspartic acid substitutions at the phosphorylation sites.

Hepatitis B virus-cell interactions and pathogenesis.

Like all viruses, hepatitis B virus (HBV) replication and pathogenesis depends on the critical interplay between viral and host factors. In this review, we will focus on the recent progress in understanding the virus-host interactions at the level of the infected cell. These interactions include the requirement of cellular chaperones for the initiation of HBV reverse transcription, the role of the HBV X protein (HBx) in modifying viral and cellular transcription and signaling, the formation of the HBV episomal DNA and its epigenetic regulation in viral persistence, and the cellular factors involved in viral entry, nucleocapsid maturation, and virion secretion.

HIV-HBV and HIV-HCV coinfection and liver cancer development.

Liver diseases caused by chronic HBV or HCV infection, including cirrhosis and HCC, are emerging as an increasingly important problem faced by millions of HIV-infected patients who are coinfected with HBV or HCV. On one hand, HIV-induced immune suppression enhances the risk of chronic viral hepatitis, increases HBV or HCV load, and may hasten the progression to cirrhosis and liver cancer. On the other hand, significant hepatotoxicity is associated with a number of antiretroviral drugs, further exacerbating liver damage associated with chronic viral hepatitis.