title: The cyclophilin-inhibitor alisporivir stimulates antigen presentation thereby promoting antigen-specific CD8(+) T cell activation.
abstract: Cyclophilin-inhibitors have potent antiviral activity against Hepatitis C virus (HCV) and are promising candidates for broad-spectrum antiviral therapy. Cyclosporine A (CsA) acts immunosuppressive by blocking T cell activation and antigen presentation. Alisporivir, a non-immunosuppressive CsA analog in clinical development, does not inhibit T cell activation. In this study we explored the impact of alisporivir on antigen presentation.
  
  
  
  Hepatoma cells endogenously expressing the epitope-restricting major histocompatibility complex-class I (MHC-I) allele HLA-A2 and constitutively expressing a viral antigen were established to study the impact of cyclophilin-inhibitors on antigen presentation. Antigen-specific CD8(+) T cell activation and MHC-I surface expression were measured to quantify antigen presentation.
  
  
  
  Our work establishes a novel cell culture model to study antigen presentation in liver-derived cells. Authentic regulation of antigen presentation was ensured by the action of pro- and anti-inflammatory cytokines. Alisporivir pretreatment stimulated antigen presentation by hepatoma target cells, leading to enhancement of antigen-specific CD8(+) T cell activation by 40%. Alisporivir, as well as a panel of other cyclophilin-inhibitors, induced an increase of MHC-I and beta-2 microglobulin on the surface of several cell lines. The drug neither enhanced MHC-I transcript or protein levels nor affected surface expression of other proteins or protein trafficking in general. Proteasome-inhibitors completely blocked the alisporivir-directed enhancement of surface MHC-I, suggesting an influence of the drug on peptide-availability.
  
  
  
  Alisporivir stimulates antigen presentation by inducing enhanced MHC-I surface expression, thereby promoting antigen-specific CD8(+) T cell activation. This immunostimulatory function might further contribute to the antiviral activity of non-immunosuppressive cyclophilin-inhibitors.
authors.affiliation: Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Esser-Nobis
authors.affiliation: Department of Medicine II, Clinic for Gastroenterology, Hepatology, Endocrinology, Infectious Diseases, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Schmidt
authors.affiliation: Department of Medicine II, Clinic for Gastroenterology, Hepatology, Endocrinology, Infectious Diseases, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Nitschke
authors.affiliation: Department of Medicine II, Clinic for Gastroenterology, Hepatology, Endocrinology, Infectious Diseases, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Neumann-Haefelin
authors.affiliation: Department of Medicine II, Clinic for Gastroenterology, Hepatology, Endocrinology, Infectious Diseases, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Thimme
authors.affiliation: Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Heidelberg, Germany. Electronic address: Volker_lohmann@med.uni-heidelberg.de.
authors.forename: Volker
authors.initials: V
authors.lastname: Lohmann
mesh_terms: D017951:Antigen Presentation / Q000187:drug effects*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D021983:Cyclophilins / Q000037:antagonists & inhibitors*; D016572:Cyclosporine / Q000494:pharmacology*; D015234:HLA-A Antigens / Q000032:analysis; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects*; D001613:beta 2-Microglobulin / Q000032:analysis
chemical_list: D015234:HLA-A Antigens; D001613:beta 2-Microglobulin; D016572:Cyclosporine; D021983:Cyclophilins; C499715:alisporivir
keywords: Antigen presentation; Cyclophilin; Cyclosporine A; Debio025; HCV; MHC-I