Baseline sensitivity of T cells to alpha-IFN correlates with sustained virological response to IFN-based triple therapy in HCV infection

SUMMARY. Chronic infection with HCV is a public health problem with approximately 170 million people infected worldwide. Interferon alpha (IFNa) sensitivity in liver and IL28B genotype has been identified as important determinants of HCV clearance in the setting of pegylated interferon/ribavirin treatment. Herein, we explored IFNa sensitivity in PBMC from 21 healthy donors and 21 HCVinfected patients treated with pegylated interferon/ribavirin and HCV nonstructural protein-3 inhibitors (i.e. telaprevir/ boceprevir). We explored phospho-STAT1 level as read-out for IFN signalling pathway activation in PBMC, T cells and monocytes and correlated results with virological response. We found that PBMC from healthy donors are desensitized to IFNa after priming and challenged with IFNa, with a subsequent decrease of phospho-STAT1 and interferonstimulated genes. Furthermore, we show that CD3+ T cells, but not monocytes, become desensitized after 4 weeks of treatment, with a significant decrease of phospho-STAT1 after ex vivo IFNa stimulation. Finally, we identified baseline phospho-STAT1 level in CD3+ T cells as a potential biomarker of sustained virological response, regardless of the IL28B genotype. In the upcoming costly era of IFN-sparing regimen, baseline IFNa sensitivity could act as biomarker to define cost-effectiveness strategies of treatment by identifying patients who will or will not respond to IFN-based treatments.