Potential capacity of interferon-α to eliminate covalently closed circular DNA (cccDNA) in hepatocytes infected with hepatitis B virus

Abstract

Interferon-alpha (IFN-α) and nucleot(s)ide analogs (NAs) are first-line drugs for the treatment of chronic hepatitis B virus (HBV) infections. Generally, NAs target the reverse transcription of HBV pregenomic RNA, but they cannot eliminate covalently-closed-circular DNA (cccDNA). Although effective treatment with NAs can dramatically decrease HBV proteins and DNA loads, and even promote serological conversion, cccDNA persists in the nucleus of hepatocytes due to the lack of effective anti-cccDNA drugs. Of the medications currently available, only IFN-α can potentially target cccDNA. However, the clinical effects of eradicating cccDNA using IFN-α in the hepatocytes of patients with HBV are not proficient as well as expected and are not well understood. Herein, we review the anti-HBV mechanisms of IFN-α involving cccDNA modification as the most promising approaches to cure HBV infection. We expect to find indications of promising areas of research that require further study to eliminate cccDNA of HBV in patients.

Keywords: Chronic HBV infection; Covalently closed circular DNA (cccDNA); Deamination; Hepatitis B virus; interferon-α.

Fig. 1

Life cycle of HBV and antiviral mechanisms of cellular innate immunity in hepatocyte. During the lifecycle of HBV, nucleic acid (RNA and DNA) can trigger innate immune system sensors (cGAS/STING, TLRs, or RIG-I) which then initiate a cascade of antiviral signaling. As a result, STATs and IRFs enter into nucleus to promote the transcription of effector genes. The most important effector proteins, IFNs, are secreted out of the cell and bind to receptors (IFNRs) on the cell surface, which then drive hundreds of ISGs to target multiple steps in the lifecycle of HBV. APOBEC3 family members activated by lym. NPC Nuclear pore complex, NTCP sodium taurocholate cotransporting polypeptide, HSPG hepatocyte-associated heparan sulfate proteoglycans, cccDNA covalently closed circular DNA, pgRNA pregenomic RNA, Pol HBV polymerase, HBs(L/M/S) HBV surface antigen (large, middle, small), HBc HBV core antigen, HBx HBV x protein, HBe HBV e antigen, NAs nucleotide analogs, IFN interferon, ISGs IFN stimulated genes, TLRs toll like receptors, RIG-I retinoic acid inducible gene I, MAD5 Melanoma differentiation-associated protein 5, cGAS cyclic GMP–AMP synthase, STING Stimulator of interferon genes. (+) stands for “activation”. (Figure created with BioRender (https://biorender.com))