PS-030-Cure of hepatitis C virus has limited impact on the functional and mitochondrial impairment of HCV-specific CD8+ T-cell responses

Abstract Background and aims Hepatitis C virus (HCV)-specific CD8+ T cells are functionally impaired in chronic hepatitis C. Even though HCV can now rapidly and sustainably be cleared from chronically infected patients, reverberation of HCV clearance on virus-specific CD8+ T cells still remains elusive. Here, we aimed to investigate if HCV clearance by direct acting antivirals (DAA) could restore the functionality of exhausted HCV-specific CD8+ T cell responses. Methods HCV-specific CD8+ T cells in PBMC obtained during and 6 months following IFN-free DAA therapy of 40 chronically HCV infected patients were analyzed for comprehensive phenotypes, proliferation, cytokine production, mitochondrial fitness and response to immune-check-point blockades. 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. 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 cell during HCV clearance was more likely in women, patients with low liver stiffness and low ALT 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-check-point inhibition. Moreover, altered mitochondrial dysfunction exhibited by exhausted HCV-specific CD8+ T cell could not be normalized after HCV clearance. Conclusion Taken together, our data implies that exhausted HCV-specific CD8+ T cells during chronic hepatitis C still remain functionally and metabolically impaired at multiple levels following HCV clearance in most patients. Our results might have implications in case of re-infection with HCV and for HCV vaccine development. Lay summary IFN-free DAAs therapy results in cure of HCV in almost all treated chronic hepatitis C patients. However, the impacts of HCV cure on immune responses remain arguable. The question if immune responses towards the virus recover is important in case of re-exposure to HCV 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 reinfections have frequently been observed.