Characterisation of healthy donor-derived T-cell responses specific to telaprevir diastereomers.

Telaprevir, a protease inhibitor, was used alongside PEGylated interferon-α and ribavirin to treat hepatitis C viral infections. The triple regimen proved successful; however, the appearance of severe skin reactions alongside competition from newer drugs restricted its use. Skin reactions presented with a delayed onset indicative of a T-cell mediated reaction. Thus, the aim of this study was to investigate whether telaprevir and/or its diastereomer, which is generated in humans, activates T-cells. Telaprevir in its S-configured therapeutic form and the R-diastereomer were cultured directly with PBMC from healthy donors prior to the generation of T-cell clones by serial dilution. Drug-specific CD4+ and CD8+ T-cell clones responsive to telaprevir and the R-diastereomer were generated and characterised in terms of phenotype and function. The clones proliferated with telaprevir and diastereomer concentrations of 5-20 µM and secreted IFN-γ, IL-13, and granzyme B. In contrast, the telaprevir M11 metabolite did not stimulate T-cells. The CD8+ T-cell response was MHC I-restricted and dependent on the presence of soluble drug. Flow cytometric analysis showed that clones expressed chemokine receptors CCR4 (skin homing) and CXCR3 (migration to peripheral tissue) and one of three distinct TCR Vβs; TCR Vβ 2, 5.1, or 22. These data show the propensity of both R- and S-forms of telaprevir to generate skin-homing cytotoxic T-cells that may induce the adverse reactions observed in human patients.