Impaired expression and function of TLR8 in chronic HBV infection and its association with treatment responses during peg-IFN-α-2a antiviral therapy

Abstract

Toll-like receptor8 (TLR8) plays an important role in controlling chronic viral infections. However, the role of TLR8 in chronic hepatitisB virus (HBV) infection is poorly understood. In this study, we aimed to investigate the expression and function of TLR8 in peripheral blood mononuclear cells (PBMCs) of chronic hepatitisB (CHB) patients and its alteration during peg-IFN-α-2a therapy. We evaluated TLR8 expression and antiviral function in vitro by real-time RT-PCR and flow cytometry analysis using fresh PBMCs obtained from CHB patients compared to healthy controls. We also employed clinical cohorts to investigate TLR8 expression in response to peg-IFN-α-2a therapy. TLR8 was mainly expressed in monocytes, and simulation with its ligand resulted in high levels of IFN-γ and TNF-α production. Compared with healthy controls, PBMCs obtained from CHB patients displayed reduced levels of TLR8 expression and IFN-γ, TNF-α and IL-12 induction. The exposure of HepG2.2.15 cells to conditioned medium from PBMCs stimulated by ssRNA40 strongly reduced the levels of HBV DNA, HBsAg and HBeAg, whereas the addition of IFN-γ or TNF-α neutralizing antibodies could block the antiviral effect. NK cells and Tcells were the principal IFN-γ-producing lymphocytes after ssRNA40 stimulation, whereas monocytes were the primary source of TNF-α. Analysis of the temporal dynamics showed that patients who achieved a complete response sustained a significant higher level of TLR8 mRNA than those who did not achieve a complete response beginning at week12 of peg-IFN-α-2a therapy. TLR8 expression and function in PBMCs were impaired by chronic HBV infection. Higher TLR8 expression after treatment week12 could potentially predict complete response to peg-IFN-α-2a therapy.