Tumor necrosis factor-alpha blockage therapy impairs hepatitis B viral clearance and enhances T-cell exhaustion in a mouse model

Abstract

Hepatitis B virus (HBV) reactivation and recurrence are common in patients undergoing immunosuppression therapy. Tumor necrosis factor (TNF) blockage therapy is effective for the treatment of many autoimmune inflammatory diseases. However, the role of TNF-a blockage therapy in the innate and adaptive immune responses against HBV is still not clear. A detailed analysis of HBV infection under TNF-a blockage therapy is essential for the prophylaxis and therapy for HBV reactivation and recurrence. In this study, HBV clearance and T-cell responses were analyzed in a HBV-transfected mouse model under anti-TNF blockage therapy. Our results demonstrated that under TNF-a blockage therapy, HBV viral clearance was impaired with persistent elevated HBV viral load in a dose-and temporal-dependent manner. The impairment of HBV clearance under anti-TNF-a blockage therapy occurred at early time points after HBV infection. In addition, TNF-a blockade maintained a higher serum HBV viral load and increased the number of intrahepatic programmed cell death (PD)-1 high CD127 low exhausted T cells. Furthermore, TNF-a blockade abolished Toll-like receptor 9 (TLR9) ligand-induced facilitation of HBV viral clearance. Taken together, TNF-a blockade impairs HBV clearance and enhances viral load, and these effects depend on early administration after HBV infection. Our results here demonstrate that early TNF-a blockade reduces viral clearance and persistently maintains elevated HBV viral load in a mouse model, suggesting that HBV may reactivate during therapy with TNF-a-blocking agents.

Tumor necrosis factor: The key to hepatitis B viral clearance

“…Furthermore, TNF-α blockade also abolishes the effects of TLR9 ligand-induced facilitation of HBV clearance. 1 Taken together, these results indicate that anti-TNF-α therapy impairs T cell functions and delays HBV clearance.…”

“…However, in a recent paper in Cell Mol Immunol, Chyuan et al reported that under TNF-α blockade, HBV viral clearance was impaired with persistent elevated HBV viral load in a dose and temporal-dependent manner. 1 It demonstrates that a deficiency of TNF-α reduces viral clearance and promotes HBV persistence in a mouse model, and the impairment of HBV clearance under anti-TNF-α occurs at an early time point of HBV infection, suggesting that HBV may reactivate during therapy with TNF inhibitors. The results together with previous reports support that TNF is a key innate cytokine required to clear HBV.…”

“…Typically, accumulated lines of evidence support that TNF-α inhibitors increase risk of HBV reactivation in patient with chronic HBV; 17,18 however, strictly controlled studies are needed to ensure the TNF-α blockage-triggered HBV reactivation. In HBV model mice, TNF-α knockout or TNF-α inhibitors reduce viral clearance, which is associated with increased number of intrahepatic PD-1highCD127low exhausted CD8+ T cells, 1,2 footnoting one of the potential mechanisms for the induced HBV reactivation. In addition, the HBV viral load was increased by anti-TNF-α Ab in a dose-dependent manner.…”

The role of tumour necrosis factor in hepatitis B infection: Jekyll and Hyde

“…40 Studies that have antagonized TNF signaling during infection have shown that this treatment causes impairment in virological control, 38, 68 a reduction in Toll-like receptor 9 activation and T-cell exhaustion. 69 …”

“…40 Studies that have antagonized TNF signaling during infection have shown that this treatment causes impairment in virological control, 38,68 a reduction in Toll-like receptor 9 activation and T-cell exhaustion. 69 The cIAP proteins are critical decision makers in determining whether TNF promotes cellular activation and survival signaling or cell death. As discussed above, in the absence of cIAPs TNF-signaling causes cell death.…”