Epigenetic regulation of hepatitis B virus covalently closed circular DNA: Implications for epigenetic therapy against chronic hepatitis B

Abstract

Hepatitis B virus (HBV) infection represents a significant public health burden worldwide. Although current therapeutics manage to control the disease progression, lifelong treatment and surveillance are required because drug resistance develops during treatment and reactivations frequently occur following medication cessation. Thus, the occurrence of hepatocellular carcinoma is decreased, but not eliminated. One major reason for failure of HBV treatment is the inability to eradicate or inactivate the viral covalently closed circular DNA (cccDNA), which is a stable episomal form of the viral genome decorated with host histones and nonhistone proteins. Accumulating evidence suggests that epigenetic modifications of cccDNA contribute to viral replication and the outcome of chronic HBV infection. Here, we summarize current progress on HBV epigenetics research and the therapeutic implications for chronic HBV infection by learning from the epigenetic therapies for cancer and other viral diseases, which may open a new venue to cure chronic hepatitis B. (Hepatology 2017;66:2066-2077).

Fig 1. HBV life cycle

The major steps in HBV life cycle including entry, trafficking, cccDNA formation, mRNA transcription, pgRNA encapsidation, DNA replication, viral particle assembly and secretion are shown. (Abbreviations: HSPG, heparan sulfate proteoglycan; MVB, multivesicular body; NTCP, sodium taurocholate cotransporting polypeptide.)

Fig 2

Schematic representation of the open reading frames (ORFs) of preC/Core, pol, preS/S, and X in HBV genome (genotype A, GenBank: AB116086); the four promoters, Cp, Sp1, Sp2, and Xp; the regulatory elements, enhancer 1 and 2 (EN1 and EN2); and three predicted CpG islands.

Fig 3. Schematic representation of modification status of HBV cccDNA-assoicated histones and the recruitment of chromatin modifying enzymes on cccDNA in relation to HBx

(A) In the presence of HBx, cccDNA-bound histones are hyperacetylated, viral minichromosome is in an open configuration and viral gene transcription is activated, leading to a high level of virus replication. (B) In the absence of HBx, host restriction factors, such as Smc5/6 complex and PRMT1, are loaded on cccDNA. The cccDNA-bound histones are hypoacetylated, viral minichromosome is in a closed configuration and viral gene is transcriptionally repressed, resulting in a low level of virus replication. (Abbreviations: H3/H4 Ac, aceylated histone 3 and 4; CBP, CREB-binding protein; PCAF, p300/CBP-associated factor; PRMT1, protein arginine methyltransferase 1 PRMT5, protein arginine methyltransferase 5; SIRT1, sirtuin 1; HDAC1, histone deaceyltransferase 1; EZH2, enhancer of zeste homolog 2; SUV39H, suppressor of variegation 3–9 Homolog; HP1: heterochromatin protein 1 factors; SETDB1: SET Domain Bifurcated 1. Smc5/6: Structural maintenance of chromosomes protein 5/6.)