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.
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Authors | Amare Aregay, Solomon Owusu Sekyere, Katja Deterding, Kerstin Port, Julia Dietz, Caterina Berkowski, Christoph Sarrazin, Michael Peter Manns, Markus Cornberg, Heiner Wedemeyer |
Journal | Journal of hepatology
(J Hepatol)
Vol. 71
Issue 5
Pg. 889-899
(11 2019)
ISSN: 1600-0641 [Electronic] Netherlands |
PMID | 31295532
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2019. Published by Elsevier B.V. |
Chemical References |
- Antiviral Agents
- Cytokines
- Reactive Oxygen Species
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Topics |
- Adult
- Aged
- Aged, 80 and over
- Antiviral Agents
(therapeutic use)
- CD8-Positive T-Lymphocytes
(drug effects, immunology, metabolism)
- Cell Proliferation
(drug effects)
- Cohort Studies
- Cytokines
(biosynthesis)
- Female
- Follow-Up Studies
- Genotype
- Hepacivirus
(drug effects, genetics)
- Hepatitis C, Chronic
(drug therapy, immunology, virology)
- Humans
- Lymphocyte Activation
(immunology)
- Male
- Middle Aged
- Mitochondria
(metabolism, pathology, virology)
- Phenotype
- Reactive Oxygen Species
(metabolism)
- Sustained Virologic Response
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