Mapping the Interactions of HBV cccDNA with Host Factors

Abstract

Hepatitis B virus (HBV) infection is a major health problem affecting about 300 million people globally. Although successful administration of a prophylactic vaccine has reduced new infections, a cure for chronic hepatitis B (CHB) is still unavailable. Current anti-HBV therapies slow down disease progression but are not curative as they cannot eliminate or permanently silence HBV covalently closed circular DNA (cccDNA). The cccDNA minichromosome persists in the nuclei of infected hepatocytes where it forms the template for all viral transcription. Interactions between host factors and cccDNA are crucial for its formation, stability, and transcriptional activity. Here, we summarize the reported interactions between HBV cccDNA and various host factors and their implications on HBV replication. While the virus hijacks certain cellular processes to complete its life cycle, there are also host factors that restrict HBV infection. Therefore, we review both positive and negative regulation of HBV cccDNA by host factors and the use of small molecule drugs or sequence-specific nucleases to target these interactions or cccDNA directly. We also discuss several reporter-based surrogate systems that mimic cccDNA biology which can be used for drug library screening of cccDNA-targeting compounds as well as identification of cccDNA-related targets.

Immune Checkpoints in Viral Infections

“…Life-long nucleoside/nucleotide analogue (NA) therapy can achieve long-term suppression of viral replication, but it cannot eliminate cccDNA. Consequently, the withdrawal of NA therapy poses the risk of viral rebound [140].…”

Liver-Derived Cell Transfection Model Efficacy for HBV Genotype B Replication/Transcription Is Determined by Complex Host Transcription Factor Network

“…[ 2 , 3 ], HBV gene expression regulation is an interplay between viral genome and host factors. Accumulating evidence suggests that precise recruitment of host transcription factors (TFs) to distinct regulatory sites on viral covalently closed circular DNA (cccDNA) leads to viral gene expression regulation [ 4 , 5 , 6 , 7 ]. HBV genome cloning and mapping of viral transcripts have led to a comprehensive understanding of the promoters (pre-core/core, X, pre-S1, and pre-S2/S promoters) and enhancers (Enh) I and II regulatory sites.…”

Posttranslational modifications of HBV core protein

“…Upon HBV entry, the viral core nucleocapsid is released from the endosome to the cyto-plasm and is transported to the nucleus, where it binds the nuclear pore complex (Rabe et al, 2003;Schmitz et al, 2010). In nucleus, the relaxed circular viral DNA (rcDNA) is repaired by host enzymes and forms a covalently closed circular DNA (cccDNA) with a typical chromatin structure consisting of histone proteins and liver-enriched as well as ubiquitous transcription factors and nuclear receptors (Koniger et al, 2014;Mohd-Ismail et al, 2019). In nucleus, HBc was suggested to regulate transcription of HBV RNAs through direct binding to cccDNA minichromosome and recruitment of cellular histone acetyltransferases (Chong et al, 2017).…”