HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chapel, C. Articles by Durantel, D. Search for Related Content PubMed PubMed Citation Articles by Chapel, C. Articles by Durantel, D. Agricola Articles by Chapel, C. Articles by Durantel, D.

Reduction of the infectivity of hepatitis C virus pseudoparticles by incorporation of misfolded glycoproteins induced by glucosidase inhibitors

¹ INSERM, U871, Université Lyon 1, et IFR62 Laennec, Lyon, France
² INSERM, U758, Ecole Normale Supérieure de Lyon, et IFR128 BioSciences Lyon-Gerland, Lyon, France
³ INSERM, ESPRI 3856, Université François Rabelais, Tours, France
⁴ Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, UK
⁵ CNRS-UPR2511, Institut de Biologie de Lille et Institut Pasteur de Lille, Lille, France

Correspondence
David Durantel
durantel{at}lyon.inserm.fr

Folding and assembly into complexes of some viral glycoproteins are exquisitely sensitive to endoplasmic reticulum (ER) -glucosidase inhibition, which prevents the trimming of glucose from N-linked glycans. Derivatives of deoxynojirimycin (DNJ) iminosugars, which are potent -glucosidase inhibitors, were shown to have antiviral activity against bovine viral diarrhea virus, a pestivirus related to hepatitis C virus (HCV). The aim of this study was to determine whether these inhibitors would affect HCV infectivity and to provide novel insights on their mechanism of action. The overall antiviral activity of glucosidase inhibitors was shown by using the two most relevant models currently available: the cell-culture model enabling complete replication of the HCV JFH1 strain in Huh7.5 cells, and infectious HCV pseudotyped particles (HCVpp) produced in HEK-293T cells that display functional E1–E2 glycoprotein complexes. By using the latter model, it is shown that the inhibition of -glucosidases by iminosugars results in the misfolding and misassembly of HCV glycoprotein pre-budding complexes. This inhibition of the assembly of E1–E2 in the ER of transfected HEK-293T cells leads to a reduction in the incorporation of E1–E2 complexes into HCVpp. More importantly, it is demonstrated that the infectivity of HCVpp that are released under treatment is reduced and that this reduction in infectivity is due to the incorporation of misfolded envelope glycoproteins in secreted particles. These properties suggest the potential usefulness of DNJ derivatives in combating HCV infection.

This article has been cited by other articles:

				S. D. Woodhouse, C. Smith, M. Michelet, N. Branza-Nichita, M. Hussey, R. A. Dwek, and N. Zitzmann Iminosugars in Combination with Interferon and Ribavirin Permanently Eradicate Noncytopathic Bovine Viral Diarrhea Virus from Persistently Infected Cells Antimicrob. Agents Chemother., May 1, 2008; 52(5): 1820 - 1828. [Abstract] [Full Text] [PDF]