Background and Aims
CD8 T cells are essential in controlling HBV infection. Viral control is dependent on efficient recognition of HBV‐infected hepatocytes by CD8 T cells, which can induce direct lysis of infected hepatocytes. In addition, CD8 T cells produce interferon (IFN)‐γ, which mediates noncytopathic viral clearance. Innate immunomodulators and HBV‐targeted RNA interference (RNAi) are being developed to treat chronic hepatitis B (CHB), but may modify HBV antigen presentation and impact CD8 T‐cell recognition, in addition to their primary mechanisms of action.
Approach and Results
HBV‐infected HepG2‐NTCP cells were treated with tenofovir disoproxil fumarate (TDF), Toll‐like receptor (TLR) 7/8 agonists, TLR7/8 conditioned media (CM) collected from immune cells, or RNAi using short interfering RNAs. The effect of these treatments on antigen presentation was measured through coculture with CD8 T cells recognizing human leukocyte antigen–A0201 restricted epitopes, HBc18‐27 or HBs183‐191. Cytokine profiles of TLR7/8 CM were measured using a cytometric bead array. TDF reduced viral replication, but not CD8 T‐cell recognition, of infected cells. Direct exposure of infected HepG2‐NTCP to TLR7/8 agonists had no impact on T‐cell recognition. Exposure of infected HepG2‐NTCP to TLR7/8 CM enhanced HBV‐specific CD8 T‐cell recognition through type 1 interferon (IFN) and IFN‐γ‐dependent mechanisms. RNAi rapidly suppressed HBV‐DNA, HBcAg, and HBsAg expression, impairing recognition by HBV‐specific CD8 T cells.
Conclusions
Immunomodulation and RNAi, but not nucleos(t)ide analogues, alter the recognition of infected HepG2‐NTCP by HBV‐specific CD8 T cells. Understanding these changes will inform combination treatments for CHB.