Immune Plasticity in Chronic Hepatitis C Virus Patients Treated With Direct-Acting Antivirals .

Functional virus-specific CD8+ T cells play a pivotal role in the outcome of hepatitis C virus (HCV) infection and are indispensable for viral control. In contrast, chronic infection is associated with T cell exhaustion and viral escape, enabling viral persistence. HCV chronic infection also seems to impact CD8+ T memory cells targeting unrelated pathogens. New, highly effective direct acting antivirals (DAA) are capable of completely clearing HCV infection and offer a unique opportunity to investigate T cell recovery after antigen clearance and the systemic effects of resolving bystander chronic infection. In this study, 21 chronic HCV patients with no prior treatment and 3 patients who previously underwent IFN-therapy were treated with DAA for three months. HCV-specific CD8+ T cells were isolated before, during, and after treatment. We studied 5 patients who completed the trial thus far using flow cytometry.^ Extensive immunophenotyping of HCV-specific CD8+ T cells find phenotypic changes compatible with reversal from T cell exhaustion. Following antigen clearance, peripheral HCV-specific CD8+ T cells targeting conserved epitopes showed marked decrease in PD1 and CD95 expression. There was also a dramatic increase in the percentage of HCV-specific CD8+ T cells expressing CD127 and CCR7, suggesting re-differentiation into memory T cells. Additionally, there was a decrease in cells expressing the terminal exhaustion marker CD39. Such changes were not observed in T cells targeting epitopes displaying sequence variation compatible with viral escape or those targeting control antigens. Intrahepatic HCV-specific CD8+ T cells also showed a decrease in PD1 and CD38 expression, while we detected less change in their memory phenotype.^ Similar patterns and changes were observed for both T cells targeting preserved and variant epitopes, suggesting persistent antigen stimulation of all T cells during infection in the liver, most likely by the continued generation of viral quasispecies with wild-type sequence. Overall, this study defines for the first time the phenotypic changes occurring in exhausted T cell after removal of antigen, in both the blood and the site of infection.