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Lack of full CD8 functional restoration after antiviral treatment for acute and chronic hepatitis C virus infection
  1. Gabriele Missale1,
  2. Massimo Pilli1,
  3. Alessandro Zerbini2,
  4. Amalia Penna1,
  5. Lara Ravanetti1,
  6. Valeria Barili1,
  7. Alessandra Orlandini1,
  8. Atim Molinari1,
  9. Massimo Fasano3,
  10. Teresa Santantonio4,
  11. Carlo Ferrari1
  1. 1Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
  2. 2Clinical Microbiology Laboratory, Department of Laboratory Medicine, Azienda Ospedaliera ASMN, Istituto di Ricovero e Cura a Carattere Scientifico, Reggio Emilia, Italy
  3. 3Clinic of Infectious Diseases, University of Bari, Bari, Italy
  4. 4Clinic of Infectious Diseases, University of Foggia, Foggia, Italy
  1. Correspondence to Dr Gabriele Missale, Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Via A Gramsci, 14, Parma 43126, Italy; missale{at}


Background Hepatitis C virus (HCV) persistence is associated with impaired CD8 functions. Whether functional restoration of CD8 T cells chronically exposed to antigen can be obtained once the antigen is removed remains to be clarified.

Objective To determine whether clearance of HCV by antiviral treatment can fully restore the antiviral function of HCV-specific CD8 cells.

Design Peripheral blood HCV-, Flu- and cytomegalovirus (CMV)-specific CD8 cells were quantified by tetramer staining in 28 patients whose HCV infection resolved after peginterferon or peginterferon/ribavirin treatment for either acute or chronic hepatitis and in eight subjects with acute HCV infection which resolved spontaneously for comparison. HCV-specific CD8 cells were evaluated for their phenotypic and functional characteristics by comparing different patient groups and CD8 cells with different viral specificities in the same patients.

Results Sustained viral response (SVR) did not lead to full maturation of a functional memory CD8 cell response. In particular, SVR in chronic infection was associated with a greater level of T cell dysfunction than responders after acute infection, who showed HCV-specific CD8 responses comparable to those of spontaneous resolvers but weaker than those of Flu-specific CD8 cells. Higher programmed death (PD)-1 expression was detected on HCV than on Flu- and CMV-specific CD8 cells and the effect of PD-1/PD-L1 blockade was better in SVRs after chronic than after acute HCV infection.

Conclusion A better restoration of HCV-specific CD8 function was detectable after SVR in patients with acute hepatitis than in those with chronic disease. Thus, the difficulty in achieving a complete restoration of the antiviral T cell function should be considered in the design of immunomodulatory therapies.

  • Immunotherapy
  • hepatitis C
  • immunology in hepatology
  • liver cirrhosis
  • hepatitis B
  • infectious disease
  • hepatitis
  • hepatitis B

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  • Funding The study was supported by a grant from Fondazione Cassa di Risparmio di Parma, Italy. Unrestricted grant from Bank Foundation.

  • Competing interests None.

  • Patient consent The manuscript does not contain personal medical information about identifiable living individuals.

  • Ethics approval Comitato Etico Unico per la Provincia di Parma, Parma, Italy.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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