HCV-Specific T-Cell Recovery After a Year of SVR Following DAA Therapy

Direct-acting antiviral (DAA) drugs lead to sustained virologic response (SVR) in almost all treated patients with chronic hepatitis C virus (HCV) infection. Despite this success, the long-term effects of HCV clearance by DAA therapy on T-cell-mediated antiviral immunity remain unclear, particularly concerning the restoration of immune function and its role in providing subsequent protection against reinfection. Our results demonstrated enhanced HCV-specific cytokine production by CD4⁺ T cells in vitro, particularly in the activated CD38⁺ and CD38⁺ HLADR⁺ subsets 1 year after DAA-mediated cure with increased frequencies of TNF-α⁺, IFNγ⁺TNF-α⁺, IL-2⁺, and IL-21⁺ cells. Notably, these subsets also exhibited reduced expressions of inhibitory markers, PD1 and TIGIT. Furthermore, reduced mitochondrial reactive oxygen species production and increased mitochondrial membrane potential were observed in CD38⁺ T helper cells, suggesting improved mitochondrial function. Significant reductions in serum IP-10, MIP-1β, and TNF-α levels were observed, indicating decreased systemic inflammation. These findings suggest that DAA-mediated HCV cure partially restores T helper cell function through reduced expression of inhibitory markers and improved mitochondrial activity in a subset of chronic HCV patients 1 year after SVR, which may potentially enhance immune protection and reduce the risk of reinfection.