title: 25-Hydroxyvitamin D3 suppresses hepatitis C virus production.
abstract: 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.
  
  
  CONCLUSIONS
  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) .
authors.affiliation: Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Matsumura
authors.forename: Takanobu
authors.initials: T
authors.lastname: Kato
authors.forename: Nao
authors.initials: N
authors.lastname: Sugiyama
authors.forename: Megumi
authors.initials: M
authors.lastname: Tasaka-Fujita
authors.forename: Asako
authors.initials: A
authors.lastname: Murayama
authors.forename: Takahiro
authors.initials: T
authors.lastname: Masaki
authors.forename: Takaji
authors.initials: T
authors.lastname: Wakita
authors.forename: Michio
authors.initials: M
authors.lastname: Imawari
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002112:Calcifediol / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016174:Hepacivirus / Q000187:drug effects* / Q000254:growth & development; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000494:pharmacology; D016133:Polymerase Chain Reaction / Q000379:methods; D012367:RNA, Viral / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012254:Ribavirin / Q000494:pharmacology; D012494:Sampling Studies; D012680:Sensitivity and Specificity
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D012367:RNA, Viral; D011994:Recombinant Proteins; D002762:Cholecalciferol; D011092:Polyethylene Glycols; D012254:Ribavirin; C417083:peginterferon alfa-2b; D002112:Calcifediol