1170 THE CYCLOPHILIN INHIBITOR SCY-635 RESTORES THE INNATE RECOGNITION OF HCV BY PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) FROM HCV POSITIVE SUBJECTS

Background and Aim: Viral immune evasion strategies lead to persistent HCV infections by interfering with the innate response to the virus and blocking the initiation of an anti-viral T cell response. In a Phase 1b clinical study in adults with chronic HCV infections, treatment with SCY-635 resulted in the induction of endogenous IFNs. More recently, a Phase 2a study demonstrated that shortterm treatment with SCY-635 enhanced the antiviral effect of PegIFN/RBV in difficult to treat, HCV genotype-1 infected subjects in a manner consistent with having ameliorated viral immune escape mechanisms and restored innate immune responses to the virus. The purpose of this study was to evaluate the ability of SCY-635 to modulate the innate immune recognition of HCV by PBMC isolated from subjects chronically infected with HCV. Method: PBMC were isolated from heparinzed blood obtained from HCV-positive subjects and HCV-negative healthy control subjects. Cells were incubated in serum free medium in the presence or absence of SCY-635 or direct acting antivirals (DAA). Stimulation with the toll-like receptor 3 agonist poly I:C was included as a positive control. Interferon and cytokine levels were determined by ELISA in supernatants taken 18h after treatment. Results: SCY-635 treatment induced the production of IFN-a, IFN-b, IFN-g and IFN-l by PBMC from chronically infected HCV subjects in a dose dependent manner. In addition, SCY-635 treated PBMC secreted IL-6 and TNF-a. PBMC from healthy HCV-negative study subjects did not produce IFNs or cytokines in response to SCY635 treatment. Treatment with poly I:C resulted in IFN-l secretion and there was an additive effect on secretion of IFN-l by addition of SCY-635 in HCV+ PBMC. Preliminary data suggest that DAAs did not induce IFN in HCV+ PBMC. Experiments to confirm these observations are ongoing. Follow up experiments to identify the cells source(s) of SCY-635-induced IFNs and inflammatory cytokines are also underway. Conclusions: Release of type I, II and III IFNs by SCY-635-treated PBMC from HCV positive subjects indicates that SCY-635 restores the innate recognition of HCV-associated molecular patterns. The data support the hypothesis that SCY-635 exerts its anti-HCV activity via modulation of the innate immune system.