Toll-like Receptor 7 and Interferon-α Synergy Establishes a Positive Feedback Loop to Potentiate Antiviral Immunity in Chronic Hepatitis B.

Background

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Objectives

Current therapies for chronic hepatitis B (CHB) rarely achieve functional cure, underscoring the need for novel immunotherapies. Toll-like receptor 7 (TLR7), a key innate immune sensor, has emerged as a major drug development focus. This study aims to characterize stage-specific TLR7 expression and functions in CHB, investigate its association with antiviral therapy response, and evaluate synergistic effects of TLR7 activation combined with interferon-α (IFN-α).

Methods

We conducted cross-sectional and longitudinal clinical analyses of CHB patients, complemented by in vitro functional assays using peripheral blood mononuclear cells (PBMCs) and purified B cells, and an in vivo HBV mouse model.

Results

TLR7 expression in PBMCs was downregulated in immunotolerant and inactive carriers but elevated in immune-active (IA) patients, positively correlated with serum ALT. TLR7 activation induced IFN-α-mediated HBV suppression, with IA patient-derived PBMCs exhibiting enhanced antiviral activity. Notably, IFN-α dose-dependently upregulated TLR7 expression, revealing a positive feedback loop between TLR7 and IFN-α. Clinically, sustained TLR7 upregulation during pegylated IFN-α therapy predicted virological response. As the primary TLR7-expressing subset, B cells exhibited enhanced proliferation, activation, cytokine production, and antibody secretion upon combined TLR7 ligand (TLR7-L)/IFN-α stimulation. In an HBV mouse model, TLR7-L/IFN-α combination therapy synergistically suppressed HBsAg and enhanced CD8+ T cell functionality.

Conclusions

This study identifies a candidate self-reinforcing TLR7-IFN-α positive feedback loop in CHB that exhibits stage-specific dynamics and predicts treatment response. The synergistic effects of TLR7 and IFN-α support a threshold model of immune activation and provide a mechanistic rationale for combination immunotherapies aiming for functional cure.