Silencing hepatitis B virus covalently closed circular DNA: The potential of an epigenetic therapy approach

Abstract

Global prophylactic vaccination programmes have helped to curb new hepatitis B virus (HBV) infections. However, it is estimated that nearly 300 million people are chronically infected and have a high risk of developing hepatocellular carcinoma. As such, HBV remains a serious health priority and the development of novel curative therapeutics is urgently needed. Chronic HBV infection has been attributed to the persistence of the covalently closed circular DNA (cccDNA) which establishes itself as a minichromosome in the nucleus of hepatocytes. As the viral transcription intermediate, the cccDNA is responsible for producing new virions and perpetuating infection. HBV is dependent on various host factors for cccDNA formation and the minichromosome is amenable to epigenetic modifications. Two HBV proteins, X (HBx) and core (HBc) promote viral replication by modulating the cccDNA epigenome and regulating host cell responses. This includes viral and host gene expression, chromatin remodeling, DNA methylation, the antiviral immune response, apoptosis, and ubiquitination. Elimination of the cccDNA minichromosome would result in a sterilizing cure; however, this may be difficult to achieve. Epigenetic therapies could permanently silence the cccDNA minichromosome and promote a functional cure. This review explores the cccDNA epigenome, how host and viral factors influence transcription, and the recent epigenetic therapies and epigenome engineering approaches that have been described.

Hepatitis B Virus Research in South Africa

“…Targeted epigenetic engineering approaches have also demonstrated anti-HBV efficacy and could be used to silence the cccDNA permanently [151]. Because viral and endogenous gene transcription is similarly regulated by host-cell pathways, the minichromosome-like structure of the cccDNA is amenable to epigenetic regulation.…”

Hepatitis B x (HBx) as a Component of a Functional Cure for Chronic Hepatitis B

“…However, when CLD progresses to fibrosis and cirrhosis, elevated levels of intrahepatic HBx accumulate [ 113 ], which promotes the persistence of virus replication, protects cells from immune-mediated elimination, and mediates the appearance of hallmarks of cancer [ 61 , 62 ]. This may contribute to why it is difficult to achieve a functional cure [ 129 ]. HBx also impacts upon protein ubiquitination, proteasome-mediated degradation [ 130 ], and apoptosis and anti-viral responses.…”

Novel Approaches to Inhibition of HBsAg Expression from cccDNA and Chromosomal Integrants: A Review

“…Zinc finger agents 44,45 In vitro Demonstrated accurate localization of DNA target sites 45 Not all sequences are available for binding; Potential for off-target cutting Gene editing Transcription activatorlike effectors nucleases (TALENs) 46,47 In vitro High precision and can specifically target any DNA sequence Potential difficulty in vivo since a large number of amino acids are required to bind to a single nucleotide Gene editing Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPRassociated (Cas) [48][49][50][51][52][53][54][55][56][57][58][59][60] In vitro Does not require engineering of a sitespecific nuclease HBV genomes are highly heterogeneous, though this mechanism has been used to excise full-length HBV genomes from a stable HBV cell line HBsAg inhibitors [61][62][63] Nucleic acid polymers (NAPs); 61 S-antigen traffic inhibiting oligonucleotide polymers (STOPS) A protein-carrier HBx vaccine showed a significant elimination of HBsAg and HBV DNA by inducing a systemic CD4+ and CD8+ T cell response in HBV carrier mice. 24 The study demonstrated that HBx-induced adaptive immunity eliminated HBV expressing cells.…”