Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF

TLDR

Toll‑like receptors initiate antiviral signaling upon ligand binding, yet many viruses evade these responses by disrupting downstream pathways, though interference with early receptor interactions has not been reported. HCV’s NS3/4A protease cleaves the adaptor TRIF, blocking TLR3‑mediated IRF‑3 and NF‑κB activation and thereby suppressing antiviral gene expression to favor chronic infection.

Abstract

Toll-like receptors (TLRs) bind pathogen-specific ligands early in infection, initiating signaling pathways that lead to expression of multiple protective cellular genes. Many viruses have evolved strategies that block the effector mechanisms induced through these signaling pathways, but viral interference with critical proximal receptor interactions has not been described. We show here that the NS3/4A serine protease of hepatitis C virus (HCV), a virus notorious for its ability to establish persistent intrahepatic infection, causes specific proteolysis of Toll-IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF or TICAM-1), an adaptor protein linking TLR3 to kinases responsible for activating IFN regulatory factor 3 (IRF-3) and NF-κB, transcription factors controlling a multiplicity of antiviral defenses. NS3/4A-mediated cleavage of TRIF reduces its abundance and inhibits polyI:C-activated signaling through the TLR3 pathway before its bifurcation to IRF-3 and NF-κB. This uniquely broad mechanism of immune evasion potentially limits expression of multiple host defense genes, thereby promoting persistent infections with this medically important virus.