Mapping the Interactions of HBV cccDNA with Host Factors.

Mohd-Ismail Mohd-Ismail,Lim Lim,Gunaratne Gunaratne,Tan Tan

doi:10.3390/ijms20174276

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.

Highlights

Viral hepatitis is a major public health concern, accounting for more than 1.3 million deaths annually [1]
Both these strategies are not curative as they do not primarily target hepatitis B virus (HBV) covalently closed circular DNA, which remains in infected hepatocytes and contributes to viral rebound after stopping treatment
Synthesis of new closed circular DNA (cccDNA) copies via both de novo infection and intracellular recycling routes require the conversion of relaxed circular DNA (rcDNA) into cccDNA

Summary

Introduction

Viral hepatitis is a major public health concern, accounting for more than 1.3 million deaths annually [1]. Compared to first-generation NAs lamivudine (LAM) and adefovir (ADV), newer drugs such as entecavir (ETV), tenofovir disoproximal fumarate (TDF) and tenofovir alafenamide (TAF) are more potent and have high barrier to resistance [4,5,6] Continuous administration of these drugs can reverse cirrhosis and reduce the risk of developing end-stage liver disease and HCC, thereby improving survival in CHB patients [7,8]. Combining NA and IFN treatments either simultaneously or sequentially have shown some promise but more long-term studies are needed to determine the optimal combination for patients with different disease backgrounds or stages [18,19] Both these strategies are not curative as they do not primarily target HBV covalently closed circular DNA (cccDNA), which remains in infected hepatocytes and contributes to viral rebound after stopping treatment. This review will mainly focus on the regulation of HBV cccDNA activity through its interactions with host factors, as well as, recently available surrogate reporter-based systems that can be used to screen for novel cccDNA inhibitors

HBV Covalently Closed Circular DNA

Eliminating cccDNA from the Infected Liver

Targeting cccDNA Transcriptional Activity

Host Restriction Factors That Directly Repress cccDNA Activity

Surrogate Systems for Screening of Anti-HBV cccDNA Drugs

Conclusions