Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Jul 28, 2016; 8(21): 902-914
Published online Jul 28, 2016. doi: 10.4254/wjh.v8.i21.902
Anti-hepatitis C virus potency of a new autophagy inhibitor using human liver slices model
Sylvie Lagaye, Sonia Brun, Jesintha Gaston, Hong Shen, Ruzena Stranska, Claire Camus, Clarisse Dubray, Géraldine Rousseau, Pierre-Philippe Massault, Jerôme Courcambeck, Firas Bassisi, Philippe Halfon, Stanislas Pol
Sylvie Lagaye, Jesintha Gaston, Stanislas Pol, Institut Pasteur, INSERM U1223, 75015 Paris, France
Sylvie Lagaye, Jesintha Gaston, Hong Shen, Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes (UMR S1016), 75014 Paris, France
Sonia Brun, Clarisse Dubray, Jerôme Courcambeck, Firas Bassisi, Philippe Halfon, Genoscience Pharma, 13006 Marseille, France
Ruzena Stranska, KU Leuven, Rega Institute, 3000 Leuven, Belgium
Claire Camus, Philippe Halfon, Laboratoire Alphabio, 13006 Marseille, France
Géraldine Rousseau, APHP, Groupe Hospitalier La Pitié Salpé­trière, Service de Chirurgie digestive et Hépato bilio pancréatique, 75013 Paris, France
Pierre-Philippe Massault, APHP, Groupe Hospitalier Cochin, Service de Chirurgie digestive, Hépato-biliaire et Endocrinienne, 75014 Paris, France
Stanislas Pol, Université Paris Descartes, 75014 Paris, France
Stanislas Pol, APHP, Groupe Hospitalier Cochin, Unité d’Hépatologie, 75014 Paris, France
Stanislas Pol, Institut Pasteur, Département de Recherche Translationnelle, INSERM UMS20, 75015 Paris, France
Author contributions: Lagaye S wrote the paper; Lagaye S, Brun S, Gaston J, Shen H, Stranska R, Camus C, Dubray C, Rousseau G, Massault PP, Courcambeck J and Bassisi F performed the experiments; Lagaye S, Brun S, Camus C, Halfon P and Pol S analyzed the data; Lagaye S, Halfon P and Pol S conceived and designed the experiments; Halfon P and Pol S contributed equally to the work.
Supported by The Institut National de la Santé et de la Recherche Médicale (INSERM, France); and the personal support of Professor Jean-François Delfraissy as Director of the French Agency, Agence Nationale de Recherches sur le Sida et les hépatites virales (ANRS).
Institutional review board statement: Institutional review board statement is not required for manuscript submission in our Institution.
Institutional animal care and use committee statement: No animal use in the experiments.
Conflict-of-interest statement: The authors have no conflict of interest to declare.
Data sharing statement: No data sharing.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Sylvie Lagaye, PhD, DSc, Senior Scientist, Institut Pasteur, INSERM U1223, 25-28 rue du Dr Roux, 75015 Paris, France. sylvie.lagaye@inserm.fr
Telephone: +33-1-40613424 Fax: +33-1-45688548
Received: March 24, 2016
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
Processing time: 111 Days and 15.6 Hours
Abstract

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.

Keywords: Host antiviral therapy; Hepatitis C virus; Tissue culture; Autophagy; Quinoline derivative

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.