Worldwide, it is estimated that more than 400 million people are currently living with chronic hepatitis B virus (HBV) infection, contributing to more than one million deaths annually as a result of liver cirrhosis and hepatocellular carcinoma (HCC). HBV DNA integrates into the cellular DNA in liver tissue of patients with chronic HBV infection and HCC. Following HBV infection, DNA methyltransferases (DNMTs) methylate any HBV DNA integrated into the human genome. This novel epigenetic mechanism enables the suppression of HBV antigens, leading to reduced viral replication. HBV is thought to induce DNA methylation via hepatitis B x (HBx) protein, which modulates cellular signalling pathways by activating DNMT 1 and 3 to benefit the virus. Activation of DNMT 1 and 3 inappropriately methylates host cellular genes including tumour suppressor genes whose disruption causes transformation of hepatocytes and hepatic malignancy. By being localised in the cytoplasm, nucleus and mitochondria of HBV-infected hepatocytes, it appears that HBx protein manages to exploit the entire body of cellular signalling pathways for viral survival and propagation. HBx protein may achieve its transcriptional transactivation action by either interacting with key genes or altering their related cellular signalling pathways or by hijacking their binding partners and taking over their roles. Although the underlying mechanisms are still unclear, processes such as cell cycle progression, calcium homeostasis, hepatic metabolism, protein ubiquitination, RNA splicing and vitamin D receptor regulation are key mechanisms that HBx protein alters to favour viral replication and cell survival. These detrimental effects would connect HBV infection to malignant transformation by inducing uncontrolled cell growth, proliferation and disrupting apoptosis.
Part of the book: Advances in Treatment of Hepatitis C and B