Functional restoration of HCV-specific T cells after antiviral treatment in patients with chronic hepatitis C

Abstract

Direct-acting antiviral (DAA) agents can successfully treat over 95% patients with chronic hepatitis C virus (HCV) infection. However, the restoration HCV-specific T-cell function following viral clearance remains unknown. I investigated functional alterations and phenotypic changes in ex vivo HCV-specific $CD8^+$ T cells of 41 patients with chronic HCV infection who were undergoing DAA treatment. As a result, significantly increased T-cell response (mainly $CD8^+$ T cells) at week 4 of treatment was observed, which was associated with the reduction of T-cell exhaustion by antigen clearance. However, this increased T-cell response diminished in later weeks. Relative to pretreatment levels, the ex vivo HCV-specific $CD8^+$ T-cell frequency decreased at 12 weeks after the end of treatment, along with a decreased antigen-experienced $CD8^+$ T-cell population. Hence, DAA-mediated viral clearance only transiently restored ex vivo T-cell function, suggesting a need to enhance ex vivo T-cell function in DAA-treated patients. Because of this necessity, I next investigated a DNA vaccine, GLS-6150, consists of plasmids encoding HCV non-structural proteins (NS3-NS5A) and adjuvant IFNL3, could enhance immune responses in persons with chronic HCV infection and investigated its associated mechanism. T-cell responses specific to NS3-NS5A were significantly increased by GLS-6150. Interestingly, frequency of regulatory T (Treg) cells, was decreased by GLS-6150, and the Treg cell frequency inversely correlated with HCV-specific T-cell responses in the study subjects. In addition, ex vivo IFN-$\lambda$3 treatment reduced Treg frequency in pre-vaccination PBMCs. Because increased Treg frequency by DAA treatment is not decreased by DAA treatment, IFNL3-adjuvanted DNA vaccination might be an effective strategy to enhance T-cell responses after viral clearance.