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

• Published in: Clinics and research in hepatology and gastroenterology Vol. 41; no. 4; pp. 386 - 398
• Main Authors: Deng, Guangying, Ge, Jun, Liu, Chao, Pang, Jinke, Huang, Zuxiong, Peng, Jie, Sun, Jian, Hou, Jinlin, Zhang, Xiaoyong
• Format: Journal Article
• Language: English
• Published: France 01.09.2017
• Subjects: Adult; Antiviral Agents - therapeutic use; Female; Gastroenterology and Hepatology; Hepatitis B, Chronic - blood; Hepatitis B, Chronic - drug therapy; Hepatitis B, Chronic - immunology; Humans; Interferon-alpha - therapeutic use; Internal Medicine; Leukocytes, Mononuclear - metabolism; Male; Middle Aged; Polyethylene Glycols - therapeutic use; Prospective Studies; Recombinant Proteins - therapeutic use; Toll-Like Receptor 8 - biosynthesis; Toll-Like Receptor 8 - physiology; Treatment Outcome; Young Adult; Healthy control; Intracellular cytokines staining; Interleukin; Limit of normal; ALT; Complete response; IFN; MFI; peg-IFN-α-2a; Peripheral blood mononuclear cell; ULN; Nature killer cells; Hepatitis B virus; TLR; HBV; Toll-like receptor; Tumor necrosis factor α; Pegylated interferon α-2a; NK cells; Hepatitis B surface antigen; IL; Conditioned medium; Mean fluorescence intensity; HBeAg; HBsAg; CM; Non-complete response; PBMC; CR; Hepatitis B e antigen; Chronic hepatitis B; TNF-α; ICS; Alanine aminotransferase; Interferon; HC; CHB; NCR
• ISSN: 2210-7401; 2210-741X
• DOI: 10.1016/j.clinre.2016.12.006

Summary Background and aim Toll-like receptor 8 (TLR8) plays an important role in controlling chronic viral infections. However, the role of TLR8 in chronic hepatitis B 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 hepatitis B (CHB) patients and its alteration during peg-IFN-α-2a therapy. Methods 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. Results 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 T cells 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 week 12 of peg-IFN-α-2a therapy. Conclusions TLR8 expression and function in PBMCs were impaired by chronic HBV infection. Higher TLR8 expression after treatment week 12 could potentially predict complete response to peg-IFN-α-2a therapy.