The cyclophilin-inhibitor alisporivir stimulates antigen presentation thereby promoting antigen-specific CD8(+) T cell activation

  • J Hepatol. 2016 Jun;64(6):1305-14. doi: 10.1016/j.jhep.2016.02.027.
Katharina Esser-Nobis  1 ,  Julia Schmidt  2 ,  Katja Nitschke  2 ,  Christoph Neumann-Haefelin  2 ,  Robert Thimme  2 ,  Volker Lohmann  3
Affiliations
  • 1. Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Heidelberg, Germany.
  • 2. Department of Medicine II, Clinic for Gastroenterology, Hepatology, Endocrinology, Infectious Diseases, University Hospital Freiburg, Freiburg, Germany.
  • 3. Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Heidelberg, Germany. Electronic address: [email protected].
PMID: 26921685 DOI: 10.1016/j.jhep.2016.02.027
Abstract

Background & aims: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords
Antigen presentation; Cyclophilin; Cyclosporine A; Debio025; HCV; MHC-I.
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