The Open Virology Journal




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ISSN: 1874-3579 ― Volume 15, 2021

Both Cyclophilin Inhibitors and Direct-Acting Antivirals Prevent PKR Activation in HCV-Infected Cells



Michael Bobardt, Udayan Chatterji, Precious Lim, Katarzyna Gawlik, Philippe Gallay*
Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA

Abstract

We and others demonstrated that the contact between NS5A and the host factor CypA is critical for HCV replication. CypI, by disrupting NS5A-CypA complexes, block HCV replication both in vitro and in patients. Since NS5A also binds to PKR, a central component of the IFN response, we investigated the possibility of a relationship between CypA, NS5A and PKR in the IFN response to HCV. HCV-infected cells treated with CypI, DAAs or IFN were analyzed for the expression and activation of various components of the innate response. We found that CypI (cyclosporine A, alisporivir, NIM811 and sanglifehrins), drastically prevented the activation/phosphorylation, but not the expression of IFN-induced PKR in HCV-infected cells. CypI had no effect on the expression or phosphorylation of other components of the innate response such as eiF2, NF-kB, IRF3, IRF9, STAT1 and STAT2, suggesting a specific effect on PKR. No significant activation of IFN-induced PKR was observed in the absence of HCV. Importantly, we found that several classes of DAAs such as NS3/4A protease, NS5B polymerase and NS5A inhibitors also prevented PKR activation. Furthermore, we found that PKR activation by the dsRNA mimic poly I:C cannot be prevented by CypI or DAAs. Our findings suggest that CypI do not have a unique effect on PKR activation, but rather the suppression of HCV replication by any anti-HCV inhibitor, abrogates PKR activation induced by IFN. Moreover, they suggest that the accumulation of dsRNA intermediates allows HCV to exploit the activation of PKR to counteract the IFN response.

Keywords: : CypI, DAAs, HCV, IFN response, NS5A, PKR..

Article Information


Identifiers and Pagination:

Year: 2014
Volume: 8
First Page: 1
Last Page: 8
Publisher Id: TOVJ-8-1
DOI: 10.2174/1874357901408010001

Article History:

Received Date: 5/1/2014
Revision Received Date: 6/3/2014
Acceptance Date: 7/3/2014
Electronic publication date: 7/3/2014
Collection year: 2014

© Bobardt et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http: //creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.


* Address correspondence to this author at the Department of Immunology & Microbial Science, IMM-9, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA; Tel: (858) 784-8180; Fax: (858) 784-8831; E-mail: gallay@scripps.edu


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