Highlights
- •HCV-specific CD8+ T cell phenotypes and functional responses are not universally restored during DAA-induced HCV clearance.
- •Mitochondrial fitness of virus-specific CD8+ T cells unaltered by cessation of persistent HCV replication.
- •In vitro immune check-point inhibition mediated selective revival of in vitro DAA unresponsive HCV-specific CD8+ T cells.
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.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: July 08, 2019
Accepted:
June 19,
2019
Received in revised form:
June 12,
2019
Received:
March 15,
2019
Identification
Copyright
© 2019 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.
