AAC Accepts, published online ahead of print on 3 March 2008

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Antimicrob. Agents Chemother. doi:10.1128/AAC.01181-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Iminosugars in combination with interferon and ribavirin permanently eradicate non-cytopathic bovine viral diarrhoea virus from persistently infected cells

Stephen D. Woodhouse, Caroline Smith, Maud Michelet, Norica Branza-Nichita, Mark Hussey, Raymond A. Dwek, and Nicole Zitzmann^*

Oxford Glycobiology Institute, Department of Biochemistry, South Parks Road, Oxford OX1 3QU, United Kingdom; and Institute of Biochemistry, Splaiul Independentei, 296, Sector 6, Bucharest 77700, Romania

^* To whom correspondence should be addressed. Email: nicole.zitzmann{at}bioch.ox.ac.uk.

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-DNJ (NN-DNJ) and N7-oxanonyl-6-deoxy-methyl-galactonojirimycin (N7-DGJ). The ability of these compounds to clear bovine viral diarrhoea virus (BVDV), a surrogate model for hepatitis C virus (HCV), from a persistently infected MDBK cell line was determined by monitoring secretion of viral RNA and the infectivity of secreted virions. In the BVDV system, after treatment with IFN/RBV alone, viral rebound is observed immediately after removal of the drugs. In contrast, we demonstrate that a triple drug combination of IFN, RBV and an iminosugar eradicates the BVDV infection in a time- and dose-dependent manner, leading to a sustained viral clearance. Importantly, in the case of NB-DNJ, the sustained viral clearance is achieved using physiologically relevant and tolerated drug concentrations. Therefore triple combination therapy including an iminosugar may prove to be of greater therapeutic value for the treatment of HCV infection than IFN/RBV alone.