Virus-host interaction mechanisms in interferon therapy for hepatitis B virus infection: recent advances

Abstract

Chronic hepatitis B virus (HBV) infection has been implicated in the development of liver diseases, such as hepatitis, fibrosis, cirrhosis, and cancer, which negatively affect the patients' quality of life and impacts a high economic strain on patients. The persistence of covalently closed circular DNA (cccDNA) allows the propagation of the infection, and no drug have been developed to completely eliminate cccDNA. The available drugs for chronic hepatitis B (CHB) are classified into nucleos(t)ide analogs (NAs) and interferon-α (IFN-α)/pegylated interferon α (Peg-IFN-α). However, these treatments do not effectively eradicate hepatitis B surface antigen (HBsAg) and their clinical efficacy is limited. The potential of IFN-based clinical cure is increasingly attracting interest from hepatologists, but the therapeutic outcomes of this intervention are suboptimal and some of them are associated with various complications. Although several novel antiviral drugs are being investigated, however, achieving a clinical cure based on monotherapy is currently challenging. The efficacy of IFN therapy is influenced by host and viral factors. This article provides a comprehensive review of host-related factors that affect the IFN therapy for CHB. A thorough understanding and management of these host-related factors will enhance the efficacy of interferon treatment, minimize adverse reactions, improve patient tolerance, and thereby increasing the clinical cure rate of hepatitis B.

Keywords: antiviral treatment; chronic hepatitis b; host factors; interferon-α; virus-host interactions.

Figure 1

Targeted Drugs in the HBV Life cycle. This figure shows the action sites of entry inhibitors. cccDNA, targeted covalently closed circular DNA; siRNA, small interfering RNA; ASO, antisense oligonucleotides; HBV, hepatitis B virus; NTCP, sodium taurocholate cotransporter peptide; EGFR, epidermal growth factor receptor; rcDNA, relaxed circular DNA; HBsAg, hepatitis B surface antigen; PrecRNA, precore mRNA; pgRNA, pregenomic RNA; preS1, presurface mRNA 1; preS2/S, presurface mRNA2/S; HBs(L/M/S), hepatitis B surface antigen (large/medium/small); NAs, nucleos(t)ide analogs.

Figure 2

The HBV life cycle and the mechanisms of action of NAs and IFN-α. HBV induces endocytosis by binding to NTCP receptor on hepatocytes, it also can bind to HSPG and EGFR and enter liver cells. After uncoating, rcDNA enters the NPC, repaired by host enzymes in the nucleus to form cccDNA. cccDNA is transcribed by host polymerases into the suite of viral RNAs that are translated into all viral proteins that are required for replication. Pregenomic RNA(pgRNA) is transcribed from cccDNA. HBc, pol and pgRNA are assembled and reverse transcribed to form rcDNA. Finally, rcDNA binds to surface antigens to form complete HBV particles and secretes. Partial rcDNA can circulate to the nucleus to increase the number of viruses. Upon viral entry into the host cells, viral nucleic acid sensor proteins, including cGAS/STING, TLRs -3, -7, -8, and −9, or RIG-I/MDA5, recognize viral DNA or RNA and generate IFNs. IFNs exert antiviral effects by inducing the host to produce IFN stimulated genes (ISGs). NTCP, sodium taurocholate cotransporter peptide; HSPG, hepatocyte-associated heparan sulfate proteoglycans; EGFR, epidermal growth factor receptor; rcDNA, relaxed circular DNA; NPC, nuclear pore complex; cccDNA, form covalently closed circular DNA; pol, polymerase; cGAS/STING, cyclic GMP-AMP synthase/stimulator of interferon genes; TLRs, Toll-like receptors; RIG-I/MDA5, retinoic acid-inducible gene I/melanoma differentiation-associated protein 5; ISGs, IFN stimulated genes; (+) stands for “activation”; 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; MX1/2, myxovirus resistance proteins1/2; APOBEC3, apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3; ISGF3, IFN-stimulating gene factor 3; IFNAR1/2, interferon-α receptor I/II; TRIM, tripartite motif protein; NOS, nitric oxide synthase; GBP1, guanylate binding protein1; IFIT1, IFN-induced tetratricopeptide repeat 1.