Elimination of hepatitis C virus has limited impact on the functional and mitochondrial impairment of HCV-specific CD8+T cell responses

Background & Aims: Hepatitis C virus (HCV)-specific CD8+ T cells are functionally impaired in chronic hepatitis C. Even though HCV can now be rapidly and sustainably cleared from chronically infected patients, the repercussions of HCV clearance on virus-specific CD8+ T cells remain elusive. Here, we aimed to investigate if HCV clearance by direct-acting antivirals (DAAs) could restore the functionality of exhausted HCV-specific CD8+ T cell responses. Methods: HCV-specific CD8+ T cells in peripheral blood were obtained from 40 patients with chronic HCV infection, during and 6 months following IFN-free DAA therapy. These cells were analyzed for comprehensive phenotypes, proliferation, cytokine production, mitochondrial fitness and response to immune-checkpoint blockade. Results: We show that, unlike activation markers that decreased, surface expression of multiple co-regulatory receptors on exhausted HCV-specific CD8+ T cells remained unaltered after clearance of HCV. Likewise, cytokine production by HCV-specific CD8+ T cells remained impaired following HCV clearance. The proliferative capacity of HCV multimer-specific CD8 + T cells was not restored in the majority of patients. Enhanced in vitro proliferative expansion of HCV-specific CD8+ T cells during HCV clearance was more likely in women, patients with low liver stiffness and low alanine aminotransferase levels in our cohort. Interestingly, HCV-specific CD8+ T cells that did not proliferate following HCV clearance could preferentially re-invigorate their proliferative capacity upon in vitro immune-checkpoint inhibition. Moreover, altered mitochondrial dysfunction exhibited by exhausted HCV-specific CD8+ T cells could not be normalized after HCV clearance. Conclusion: Taken together, our data implies that exhausted HCV-specific CD8+ T cells remain functionally and metabolically impaired at multiple levels following HCV clearance in most patients with chronic hepatitis C. Our results might have implications in cases of re-infection with HCV and for HCV vaccine development. Lay summary: Direct-acting antiviral therapy results in cure of hepatitis C virus (HCV) in almost all treated patients. However, the impacts of HCV cure on immune responses remain controversial. Whether immune responses to HCV recover is important in cases of re-exposure, or for the resolution of extrahepatic manifestations. The main finding of our study was that HCV-specific T cells remain functionally impaired despite HCV clearance. This finding could explain the fact that HCV cure does not lead to protective immunity and that re-infections have frequently been observed. (C) 2019 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.