Hepatitis C Virus Core Protein Induces Homotolerance and Cross-Tolerance to Toll-Like Receptor Ligands by Activation of Toll-Like Receptor 2

Background. Hepatitis C virus (HCV) activates host innate immune responses mediated by retinoic acid inducing gene-I (RIG-I) and Toll-like receptors (TLRs). Although the nonstructural protein 3/4A (NS3/4A) of HCV disrupts interferon responses by inhibiting RIG-I signaling, the effects of TLR activation by HCV-associated proteins on host innate immune responses are poorly understood. Methods. Proinflammatory cytokine responses to various TLR ligands in human antigen-presenting cells (APCs) were examined either with or without prestimulation by HCV core protein. Results. TLR2 activation by the HCV core protein leads to a decrease in interleukin 6 (IL-6) production by human APCs after subsequent stimulation with TLR2 (homotolerance) ligands and TLR4 (cross-tolerance) ligands. This hyporesponsiveness induced by preexposure to the HCV core protein was partially mediated by the negative regulation of nuclear factor-kappa B activation by the induction of IRAK-M. TLR ligand-induced IL-6 production was significantly reduced in peripheral blood monocytes isolated from HCV-infected patients, compared with those of healthy control subjects. Alloantigen presentation by monocytes isolated from HCV-infected patients results in impaired production of interleukin 17 by naive CD4(+) T cells in the presence of TLR ligands. Conclusions. Chronic stimulation of APCs with HCV core protein is associated with hyporesponsiveness in TLR-mediated innate immunity.