Intracellular interferon signalling pathways as potential regulators of covalently closed circular DNA in the treatment of chronic hepatitis B

Abstract

Infection with the hepatitis B virus (HBV) is still a major global health threat as 250 million people worldwide continue to be chronically infected with the virus. While patients may be treated with nucleoside/nucleotide analogues, this only suppresses HBV titre to sub-detection levels without eliminating the persistent HBV covalently closed circular DNA (cccDNA) genome. As a result, HBV infection cannot be cured, and the virus reactivates when conditions are favorable. Interferons (IFNs) are cytokines known to induce powerful antiviral mechanisms that clear viruses from infected cells. They have been shown to induce cccDNA clearance, but their use in the treatment of HBV infection is limited as HBV-targeting immune cells are exhausted and HBV has evolved multiple mechanisms to evade and suppress IFN signalling. Thus, to fully utilize IFN-mediated intracellular mechanisms to effectively eliminate HBV, instead of direct IFN administration, novel strategies to sustain IFN-mediated anti-cccDNA and antiviral mechanisms need to be developed. This review will consolidate what is known about how IFNs act to achieve its intracellular antiviral effects and highlight the critical interferon-stimulated gene targets and effector mechanisms with potent anti-cccDNA functions. These include cccDNA degradation by APOBECs and cccDNA silencing and transcription repression by epigenetic modifications. In addition, the mechanisms that HBV employs to disrupt IFN signalling will be discussed. Drugs that have been developed or are in the pipeline for components of the IFN signalling pathway and HBV targets that detract IFN signalling mechanisms will also be identified and discussed for utility in the treatment of HBV infections. Together, these will provide useful insights into design strategies that specifically target cccDNA for the eradication of HBV.

Keywords: Covalently closed circular DNA; Interferons; APOBECs; Epigenetic modification; Hepatitis B virus therapeutics

Core Tip: Hepatitis B virus (HBV) infection remains an incurable disease affecting millions worldwide. Treatment with interferons (IFNs) can eliminate the virus by clearing its persistent genome, covalently closed circular DNA (cccDNA), from infected cells. However, its clinical efficacy is limited as HBV proteins antagonize IFN signalling. Other current therapeutics do not target cccDNA thus cannot eliminate HBV. Therefore, new drugs based on the knowledge of how IFNs cause cccDNA degradation and silencing, as well as insights into how HBV antagonizes IFN-mediated mechanisms are needed. This review summarizes what is known about these processes and highlights drugs and developing therapeutics targeted against them for HBV eradication.