Abstract
Numerous canonical cellular signaling pathways modulate hepatitis B virus (HBV) replication. HBV genome products are known to play a significant role in regulating these cellular pathways for the liver’s viral-related pathology and physiology and have been identified as the main factor in hepatocarcinogenesis. Signaling changes during viral replication ultimately affect cellular persistence, multiplication, migration, genome instability, and genome damage, leading to proliferation, evasion of apoptosis, block of differentiation, and immortality. Recent studies have documented that numerous signaling pathway agonists or inhibitors play an important role in reducing HBV replication in vitro and in vivo, and some have been used in phase I or phase II clinical trials. These optional agents as molecular therapeutics target cellular pathways that could limit the replication and transcription of HBV or inhibit the secretion of the small surface antigen of HBV in a signaling-independent manner. As principle-based available information, a combined strategy including antiviral therapy and immunomodulation will be needed to control HBV infection effectively. In this review, we summarize recent findings on interventions of molecular regulators in viral replication and the interactions of HBV proteins with the components of the various targeting cellular pathways, which may assist in designing novel agents to modulate signaling pathways to prevent HBV replication or carcinogenesis.
Highlights
Hepatitis B virus (HBV) is a DNA virus with a partially doublestranded DNA genome that is circular and contains ~3.2 kb genome in length, encoding seven different proteins, such as HBV surface antigen (HBsAg), HBV core antigen (HBcAg), HBV e antigen (HBeAg), and the transcriptional transactivator HBV X protein (HBx), which controls HBV transcription from covalently closed circular DNA (Tu et al, 2017)
It has been shown that the nuclear factors of activated T cells 3 (NFATc3) inhibit hepatocarcinogenesis and HBV replication by positively regulating retinoic acid-inducible gene I (RIG-I)-mediated IFN transcription (Zao et al, 2021). These findings collectively reveal a novel regulatory signaling cascade, the RIG-I/NFATc3/IFNs axis, which inhibits HBV replication and hepatocarcinogenesis by enhancing the hepatocytes functional axis’s immune responses, which might potentially be exploited for therapeutic benefits in the clinical treatment of HBV-related hepatocellular carcinoma (HCC)
Studies demonstrated that MLN4924 could block neddylation and activates the extracellular signal-modulated kinase (ERK) signaling pathway to inhibit the expression of several transcription factors required for HBV replication (Xie et al, 2021), and the Forkhead box O 4 (FoxO4) transcription factor plays an important role in inhibiting HBV core promoter activity through ERK-mediated hepatocyte nuclear factor-4a (HNF4a) down-regulation in vivo (Li et al, 2019a)
Summary
Hepatitis B virus (HBV) is a DNA virus with a partially doublestranded DNA genome that is circular and contains ~3.2 kb genome in length, encoding seven different proteins, such as HBV surface antigen (HBsAg), HBV core antigen (HBcAg), HBV e antigen (HBeAg), and the transcriptional transactivator HBV X protein (HBx), which controls HBV transcription from covalently closed circular DNA (cccDNA) (Tu et al, 2017). Recommended therapeutic agents for the treatment of chronic HBV infection, including current agents, nucleos(t)ide analogs (NAs), and pegylated-interferon alfa (peg-IFN-a), have been approved to inhibit HBV DNA replication, which can interrupt or prevent the risk of developing cirrhosis and hepatocellular carcinoma (European Association for the Study of the Liver, 2017). Combination therapy, including the TLR9 agonist [CpG oligodeoxynucleotides (ODNs)] and entecavir, induce early antiviral responses and enhance inhibition of viral replication in a woodchuck model of chronic hepadnaviral infection, but neither of these agents can be used alone, suggesting that they are synergistic (Meng et al, 2016). A small-molecule compound, F7, and 5′-triphosphate-poly-U/UC PAMP RNA
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