Interferon-α–Induced TRAIL on Natural Killer Cells Is Associated With Control of Hepatitis C Virus Infection

Background & Aims Pegylated interferon-α (PEG-IFNα), in combination with ribavirin, controls hepatitis C virus (HCV) infection in approximately 50% of patients by mechanisms that are not completely understood. Beside a direct antiviral effect, different immunomodulatory effects have been discussed. Natural killer (NK) cells might be associated with control of HCV infection. We examined the effects of IFNα on human NK cells and its relevance to HCV infection. Methods We performed gene expression profiling studies of NK cells following stimulation of peripheral blood mononuclear cells with IFNα. We evaluated IFNα-induced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression using flow cytometry analyses of NK cells isolated from patients with acute or chronic hepatitis C that had received PEG-IFNα therapy. Results TRAIL was among the most up-regulated genes after IFNα stimulation of NK cells from healthy controls. After in vitro stimulation with IFNα, CD56 dim NK cells from patients who had responded to PEG-IFNα therapy expressed higher levels of TRAIL than cells from patients with chronic hepatitis C. TRAIL expression, ex vivo, was inversely correlated with HCV-RNA levels during the early phase of PEG-IFNα therapy. In patients with acute hepatitis C, TRAIL expression on CD56 bright NK cells increased significantly compared with cells from controls. In in vitro studies, IFNα-stimulated NK cells eliminated HCV-replicating hepatoma cells by a TRAIL-mediated mechanism. Conclusions IFNα-induced expression of TRAIL on NK cells is associated with control of HCV infection; these observations might account for the second-phase decline in HCV-RNA levels during PEG-IFNα therapy.