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

BACKGROUND & AIMS: Pegylated interferon-alpha (PEG-IFN alpha), in combination with ribavirin, controls hepatitis C virus (HCV) infection in approximately SO% of patients by mechanisms that are not completely understood. Beside a direct antiviral effect, different immunomodulatoty effects have been discussed. Natural killer (NK) cells might be associated with control of HCV infection. We examined the effects of IFN alpha 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 IFN alpha. We evaluated IFN alpha-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-IFN alpha therapy. RESULTS: TRAIL was among the most up-regulated genes after IFN alpha stimulation of NK cells from healthy controls. After in vitro stimulation with IFN alpha, CD56(dim) NK cells from patients who had responded to PEG-IFN alpha 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-IFN alpha 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, IFN alpha-stimulated NK cells eliminated HCV-replicating hepatoma cells by a TRAIL-mediated mechanism. CONCLUSIONS: IFN alpha-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-IFN alpha therapy.