The Epigenetic Control of Hepatitis B Virus Modulates the Outcome of Infection

Abstract

Epigenetic modifications are stable alterations in gene expression that do not involve mutations of the genetic sequence itself. It has become increasingly clear that epigenetic factors contribute to the outcome of chronic hepatitis B virus (HBV) infection by affecting cellular and virion gene expression, viral replication and the development of hepatocellular carcinoma. HBV persists in the nucleus of infected hepatocytes as a stable non-integrated covalently closed circular DNA (cccDNA) which functions as a minichromosome. There are two major forms of HBV epigenetic regulation: posttranslational modification of histone proteins associated with the cccDNA minichromosome and DNA methylation of viral and host genomes. This review explores how HBV can interphase with host epigenetic regulation in order to evade host defences and to promote its own survival and persistence. We focus on the effect of cccDNA bound-histone modifications and the methylation status of HBV DNA in regulating viral replication. Investigation of HBV epigenetic control has important clinical correlates with regards to the development of potential therapeutic regimens that will successfully eradicate HBV infection and deal with HBV reactivation in those undergoing treatment with demethylating agents.

Hepatitis B virus basal core promoter mutations show lower replication fitness associated with cccDNA acetylation status

“…We demonstrated that one third of the CpG islands within the cccDNA region were methylated independently of the presence of mutations. Our results are in agreement with previous studies showing that cccDNA is a target for methylation (Vivekanandan et al, 2010;Koumbi et al, 2015). CccDNA methylation was accompanied by increased levels of cellular DNMT1 expression and the recruitment of DNMT1 onto cccDNA.…”

“…The methylation of episomal cccDNA in human tissue of CHB patients has been associated with impaired cccDNA mRNA synthesis capability and suppressed viral gene expression (Guo et al, 2009;Vivekanandan et al, 2010;Koumbi et al, 2015). It has been reported that DNMT1, DNMT2 and DNMT3 expression is upregulated in response to HBV, leading to viral methylation and decreased viral replication (Liu et al, 2009;Vivekanandan et al, 2010).…”

“…Cumulative evidence shows that HBV replication is regulated by epigenetic modifications (Pollicino et al, 2006;Guo et al, 2009;Vivekanandan et al, 2010;Koumbi et al, 2015). In the nuclei of infected hepatocytes, HBV DNA associates with histones combined with HBcAg to form cccDNA minichromosomes (Bock et al, 2001).…”

Overview of biological mechanisms of human carcinogens

“…Specific microRNAs, reported to be associated with various aspects of hepatitis B biology were classified and their role in multiple aspects related to HBV was defined (Sarkar and Chakravarty 2015). Epigenetic changes induced by the HBx protein include aberrations in DNA methylation, post-translational modification of histones, microRNA expression, and epigenetic control of HBV covalently closed circular DNA (cccDNA) (Koumbi and Karayiannis 2015;Tian and Ou 2015;Tian et al 2013). Single-nucleotide polymorphisms (SNPs) in the genes encoding miR-146a and miR-196a-2 influence susceptibility to HCC from HBV infection ).…”

Virus–host interplay in hepatitis B virus infection and epigenetic treatment strategies

“…Hepatitis B virus‐induced epigenetic alterations represent novel therapeutic targets for the prevention of HBV‐associated HCC development and progression. DNA methylation and post‐translational histone modifications are the most studied epigenetic marks altered by viral infections that can be medically modified using so‐called epidrugs. To date, malignancy remains to be the pivotal domain for the clinical implication of epidrug treatments in humans .…”