Persistent infection with hepatitis C virus (HCV) is a major cause of chronic hepatitis in humans. In chronic carriers, the viral infection induces liver damage that predisposes the patient for cirrhosis and can lead to hepatocellular carcinoma. Current chemotherapies are limited to alpha interferon (IFN-␣) used either alone or in combination with ribavirin (RBV). In addition to its limited efficacy, this treatment is frequently poorly tolerated because of its side effects. The urgently needed development of new drugs is made difficult by the lack of an in vitro or in vivo infectivity model, and no cell line has been found so far to reliably and reproducibly support HCV infection. For this reason, the closely related pestivirus bovine viral diarrhea virus (BVDV) has sometimes been used as a surrogate in vitro infectivity model. In this study we used an MDBK cell line persistently infected with noncytopathic BVDV to assess the antiviral effect of IFN-␣ and RBV, the two drugs currently in clinical use against HCV. The same system was then used to evaluate the potential of two classes of iminosugar derivates to clear noncytopathic BVDV infection from MDBK cells. We show that treatment with long-alkyl-chain deoxynojirimycin derivatives, which are inhibitors of the endoplasmic reticulum (ER)-resident ␣-glucosidases, can greatly reduce the amount of secreted enveloped viral RNA. Long-alkyl-chain deoxygalactonojirimycin derivatives, which do not inhibit ER ␣-glucosidases, were less potent but still more effective in this system than IFN-␣ or ribavirin.
Hepatitis C virus (HCV) causes persistent infection in ap-proximately 70 to 80% of people infected and is responsible for liver injuries that can lead to cirrhosis and hepatocellular carcinoma (2, 34). While current therapeutic strategies against HCV infection rely mainly on either naked or pegylated alpha interferon (IFN-␣) alone or in combination with ribavirin (RBV) (19,28,34,37,43), considerable efforts are being made to develop new molecules which show better efficacy, particularly for refractory patients, who represent on average 50% of patients treated (19,28,34,42,43). Depending on the HCV genotype, the percentage of refractory patient varies from 80% (genotype 1b) to 20% (genotype 3).Molecules targeting viral activities, such as protease-or polymerase-specific inhibitors, are traditionally the most attractive candidates for drug development, though this strategy faces resistance problems, especially when dealing with fastmutating viruses like HCV and human immunodeficiency virus. The problem of drug-resistant viral escape mutants has also been observed for hepatitis B virus (13,18,35,36). Alternatively, a host cell target could be chosen which would have to be more important for the survival of the virus than for that of the host. Such a target would arguably be more difficult for the virus to mutate around.The feasibility of such an approach has recently been investigated with deoxynojirimycin (DNJ)-based iminosugar derivatives as antiviral agents (6,7,17,29,30...