title: Iminosugars in combination with interferon and ribavirin permanently eradicate noncytopathic bovine viral diarrhea virus from persistently infected cells.
abstract: We evaluated interferon (IFN) and ribavirin (RBV) as dual therapy and as part of triple-combination therapies with the iminosugars N-butyl-deoxynojirimycin (NB-DNJ), N-nonyl-deoxynojirimycin, and N-7-oxanonyl-6-deoxymethyl-galactonojirimycin. The ability of these compounds to clear bovine viral diarrhea virus (BVDV), a surrogate model for hepatitis C virus (HCV), from a persistently infected Madin-Darby bovine kidney cells cell line was determined by monitoring the secretion of viral RNA and the infectivity of secreted virions. In the BVDV system, after treatment with IFN-RBV alone, viral rebound was observed immediately after removal of the drugs. In contrast, we demonstrate that a triple drug combination of IFN, RBV, and an iminosugar eradicated the BVDV infection in a time- and a dose-dependent manner, leading to sustained viral clearance. Importantly, in the case of NB-DNJ, the sustained viral clearance was achieved by using physiologically relevant and tolerated drug concentrations. Therefore, the use of a triple-combination therapy that includes an iminosugar may prove to be of greater therapeutic value for the treatment of HCV infection than the use of IFN-RBV alone.
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, South Parks Road, Oxford OX1 3QU, United Kingdom.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Woodhouse
authors.forename: Caroline
authors.initials: C
authors.lastname: Smith
authors.forename: Maud
authors.initials: M
authors.lastname: Michelet
authors.forename: Norica
authors.initials: N
authors.lastname: Branza-Nichita
authors.forename: Mark
authors.initials: M
authors.lastname: Hussey
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Dwek
authors.forename: Nicole
authors.initials: N
authors.lastname: Zitzmann
mesh_terms: D017485:1-Deoxynojirimycin / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002460:Cell Line; D001908:Diarrhea Viruses, Bovine Viral / Q000187:drug effects* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D007372:Interferons / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012254:Ribavirin / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000998:Antiviral Agents; D012367:RNA, Viral; C501633:deoxynojirimycine; D017485:1-Deoxynojirimycin; D012254:Ribavirin; D007372:Interferons; D005944:Glucosamine