IMPACT OF HEPATITIS C VIRUS CORE PROTEIN ON THE TUMOR NECROSIS FACTOR APOPTOSIS-INDUCING LIGAND PATHWAY IN PERIPHERAL BLOOD MONONUCLEAR CELLS
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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 dissertation, 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 hours to determine how HCV core protein affects the total PBMC population and critical innate immune cells (i.e., plasmacytoid dendritic cells (pDCs) and natural killer (NK) cells). We measured the relative expression of TRAIL, TRAIL-R1, and TRAIL-R2 in PBMCs, pDCs, and NK cells. We report that HCV core protein causes increased expression of both membrane-bound and soluble forms of TRAIL-R1 and TRAIL-R2 in the total PBMCs population and in pDCs. We also show that TRAIL interacts with TRAIL-R1 and TRAIL-R2 after cleavage of membrane-bound TRAIL yielding soluble TRAIL. Our results indicate that HCV core protein increases PBMC and pDC susceptibility to apoptosis and may cause increased TRAIL pathway activity within 12 hours of infection. In addition, we observed that increased death receptor expression in PBMCs and pDCs may contribute to an impaired immune response and HCV pathogenesis, as typically observed in chronically HCV-infected individuals.