25‐hydroxyvitamin D 3 suppresses hepatitis C virus production

Because the current interferon (IFN)‐based treatment for hepatitis C virus (HCV) infection has a therapeutic limitation and side effects, a more efficient therapeutic strategy is desired. Recent studies show that supplementation of vitamin D significantly improves sustained viral response via IFN‐based therapy. However, mechanisms and an active molecular form of vitamin D for its anti‐HCV effects have not been fully clarified. To address these questions, we infected HuH‐7 cells with cell culture‐generated HCV in the presence or absence of vitamin D 3 or its metabolites. To our surprise, 25‐hydroxyvitamin D 3 [25(OH)D 3 ], but not vitamin D 3 or 1,25‐dihydroxyvitamin D 3 , reduced the extra‐ and intracellular levels of HCV core antigen in a concentration‐dependent manner. Single‐cycle virus production assay with a CD81‐negative cell line reveals that the inhibitory effect of 25(OH)D 3 is at the level of infectious virus assembly but not entry or replication. Long‐term 25(OH)D 3 treatment generates a HCV mutant with acquired resistance to 25(OH)D 3 , and this mutation resulting in a N1279Y substitution in the nonstructural region 3 helicase domain is responsible for the resistance. Conclusion: 25(OH)D 3 is a novel anti‐HCV agent that targets an infectious viral particle assembly step. This finding provides insight into the improved efficacy of anti‐HCV treatment via the combination of vitamin D 3 and IFN. Our results also suggest that 25(OH)D 3 , not vitamin D 3 , is a better therapeutic option in patients with hepatic dysfunction and reduced enzymatic activity for generation of 25(OH)D 3 . (H EPATOLOGY 2012)