Published online Jul 28, 2016. doi: 10.4254/wjh.v8.i21.902
Peer-review started: April 6, 2016
First decision: May 16, 2016
Revised: June 1, 2016
Accepted: June 27, 2016
Article in press: June 29, 2016
Published online: July 28, 2016
AIM: To evaluate the antiviral potency of a new anti-hepatitis C virus (HCV) antiviral agent targeting the cellular autophagy machinery.
METHODS: Non-infected liver slices, obtained from human liver resection and cut in 350 μm-thick slices (2.7 × 106 cells per slice) were infected with cell culture-grown HCV Con1b/C3 supernatant (multiplicity of infection = 0.1) cultivated for up to ten days. HCV infected slices were treated at day 4 post-infection with GNS-396 for 6 d at different concentrations. HCV replication was evaluated by strand-specific real-time quantitative reverse transcription - polymerase chain reaction. The infectivity titers of supernatants were evaluated by foci formation upon inoculation into naive Huh-7.5.1 cells. The cytotoxic effect of the drugs was evaluated by lactate dehydrogenase leakage assays.
RESULTS: The antiviral efficacy of a new antiviral drug, GNS-396, an autophagy inhibitor, on HCV infection of adult human liver slices was evidenced in a dose-dependent manner. At day 6 post-treatment, GNS-396 EC50 was 158 nmol/L without cytotoxic effect (compared to hydroxychloroquine EC50 = 1.17 μmol/L).
CONCLUSION: Our results demonstrated that our ex vivo model is efficient for evaluation the potency of autophagy inhibitors, in particular a new quinoline derivative GNS-396 as antiviral could inhibit HCV infection in a dose-dependent manner without cytotoxic effect.
Core tip: Hepatitis C virus (HCV) infection (or spread) is a serious public health challenge counting approximately 170 million people that are chronically infected worldwide. Efficient interferon-free treatments with new direct acting antivirals are expected to cure more than 90% of HCV-infected patients but they are not available in all the countries. Autophagy machinery is required to initiate HCV replication. Host antiviral therapy is an additional option for the treatment of HCV infection. The new autophagy inhibitor GNS-396 demonstrated significant efficacy and additive activity in inhibiting HCV replication and might be an additional option to treat HCV infected individuals.