Abstract
Chronic hepatitis B virus (CHB) infection remains a major global public health issue for which there is still lacking effective curative treatment. Interferon-α (IFN-α) and its pegylated form have been approved as an anti-HBV drug with the advantage of antiviral activity and host immunity against HBV infection enhancement, however, IFN-α treatment failure in CHB patients is a challenging obstacle with 70% of CHB patients respond poorly to exogenous IFN-α treatment. The IFN-α treatment response is negatively regulated by both viral and host factors, and the role of viral factors has been extensively illustrated, while much less attention has been paid to host negative factors. Here, we summarized evidence of host negative regulators and parameters involved in IFN-α therapy failure, review the mechanisms responsible for these effects, and discuss the possible improvement of IFN-based therapy and the rationale of combining the inhibitors of negative regulators in achieving an HBV cure.
Highlights
Chronic hepatitis B virus (CHB) infection affects more than 290 million people worldwide, with 1.5 million new infections each year, estimated by World Health Organization [1]
It is summarized that females are more likely to achieve hepatitis B e antigen (HBeAg) seroconversion after IFN therapy comparing to males [10, 139], which may be an effect of sex hormones
Identifying and inhibiting the pathways or molecules that negatively regulate IFN-α signaling and therapy, as well as finding host parameters that predict the response of patients with CHB to antiviral therapy are obvious ways to improve the efficacy of IFN-α
Summary
Chronic hepatitis B virus (CHB) infection affects more than 290 million people worldwide, with 1.5 million new infections each year, estimated by World Health Organization [1]. IFN- α binds to its receptor (IFN-α/β-receptor, IFNAR) leading to the downstream signaling pathway and result in the expression of various IFN-stimulated genes (ISGs), which have multiple functions including anti-viral, anti-proliferation, anti-tumor, and immunomodulation Some of these directly inhibit virus transcription and translation, others function as host immune modulators by NK cells activation, Dendritic cells (DCs) maturation, CD8+ T-cell augmentation, and B cell response [19]. Type I IFN can activate other important members of innate immunity, including natural killer (NK) cells and natural killer T (NKT) cells, recruiting them to the infected tissues and recognize infected hepatocytes These immune cells secrete cytokines that promote intracellular HBV clearance and induce apoptosis. The antiviral effect against HBV of IFN and its immunomodulatory function have been finely summarized in several reviews [22, 31, 34]
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