Amare Aregay1, Solomon Owusu Sekyere1, Katja Deterding2, Kerstin Port1, Julia Dietz3, Caterina Berkowski3, Christoph Sarrazin3, Michael Peter Manns4, Markus Cornberg5, Heiner Wedemeyer6. 1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. 2. Department of Gastroenterology and Hepatology, Essen University Hospital, Essen, Germany. 3. German Centre for Infection Research (DZIF), External Partner Site Frankfurt, Germany; Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany. 4. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; German Centre for Infection Research, Hannover, Germany (DZIF), Partner-site Hannover-Braunschweig, Germany. 5. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; German Centre for Infection Research, Hannover, Germany (DZIF), Partner-site Hannover-Braunschweig, Germany; Centre for Individualised Infection Medicine (CIIM), Hannover, Germany. 6. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; German Centre for Infection Research, Hannover, Germany (DZIF), Partner-site Hannover-Braunschweig, Germany; Department of Gastroenterology and Hepatology, Essen University Hospital, Essen, Germany; Integrated Research and Treatment Centre Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany. Electronic address: Gastroenterology@uk-essen.de.
Abstract
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.
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 infectedpatients, 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.
Authors: Paula Martínez-Román; Celia Crespo-Bermejo; Daniel Valle-Millares; Violeta Lara-Aguilar; Sonia Arca-Lafuente; Luz Martín-Carbonero; Pablo Ryan; Ignacio de Los Santos; María Rosa López-Huertas; Claudia Palladino; María Muñoz-Muñoz; Amanda Fernández-Rodríguez; Mayte Coiras; Verónica Briz Journal: J Clin Med Date: 2022-06-21 Impact factor: 4.964
Authors: Katie Healy; Anna Pasetto; Michał J Sobkowiak; Chai Fen Soon; Markus Cornberg; Soo Aleman; Margaret Sällberg Chen Journal: Cells Date: 2020-06-16 Impact factor: 6.600