Investigation of the bi-directional relationship between natural killer (NK) cells and plasmacytoid dendritic cells (pDCs) is critical in understanding antiviral immunity. In the present study, we determined whether the tumor necrosis factor apoptosis-inducing ligand (TRAIL) pathway was responsible for increased apoptosis of pDCs in hepatitis C virus (HCV) infection. We stimulated peripheral blood mononuclear cells (PBMCs) with recombinant HCV core protein within 12 hours to measure the relative expression of tumor necrosis factor apoptosis-inducing receptor 1 (TRAIL-R1) and TRAIL-R2 in pDCs using flow cytometry and image cytometry. We also measured the relative expression of TRAIL in NK cells after stimulation with recombinant HCV core protein using flow cytometry and image cytometry. Using flow cytometry, our results show that within 12 hours of stimulation, HCV core protein increases TRAIL-R1 on pDCs by 0.01%, CD56 expression by 0.66%, and TRAIL expression by 0.66%, in NK cells as compared to unstimulated PBMCs. ELISA and fluorescence spectroscopy results showed that HCV core protein decreases Bcl-2 expression in PBMCs and in pDCs by 36% and 3%, respectively. Our results suggest that HCV core protein increases NK cell deletion of pDCs, independent of the Bcl-2 pathway, contributing to HCV viral escape from immune responses, which may result in chronic HCV infection.

A robust innate and adaptive immune response is essential to viral clearance. Hepatitis C virus (HCV) infection typically leads to alteration of the innate and adaptive immune response, which is caused by interaction of HCV core protein with various host factors. It is important to investigate the alterations to the immune response during the transition from acute HCV to chronic HCV infection to develop better therapeutic methods for HCV infection. In this work, to determine whether HCV viral persistence occurs via tumor necrosis apoptosis-inducing ligand (TRAIL)-mediated apoptosis, we stimulated peripheral blood mononuclear cells (PBMCs) with recombinant HCV core protein within 12 h to measure the relative expression of death receptors 4 and 5 (DR4 and DR5) in PBMCs. We show that recombinant HCV core protein causes increased DR4 and DR5 expression in PBMCs. We also show that TRAIL interacts with DR4 and DR5 after cleavage of membrane-bound TRAIL yielding soluble TRAIL. Our results show that HCV core protein increases PBMC susceptibility to apoptosis and may cause increased TRAIL pathway activity within 12 h of infection. In addition, we observed that increased death receptor expression may contribute to HCV pathogenesis, as typically observed in chronically HCV-infected individuals.