title: Vitamin D: an innate antiviral agent suppressing hepatitis C virus in human hepatocytes.
abstract: Vitamin D supplementation was reported to improve the probability of achieving a sustained virological response when combined with antiviral treatment against hepatitis C virus (HCV). Our aim was to determine the in vitro potential of vitamin D to inhibit HCV infectious virus production and explore the mechanism(s) of inhibition. Here we show that vitamin D(3) remarkably inhibits HCV production in Huh7.5 hepatoma cells. These cells express CYP27B1, the gene encoding for the enzyme responsible for the synthesis of the vitamin D hormonally active metabolite, calcitriol. Treatment with vitamin D(3) resulted in calcitriol production and induction of calcitriol target gene CYP24A1, indicating that these cells contain the full machinery for vitamin D metabolism and activity. Notably, treatment with calcitriol resulted in HCV inhibition. Collectively, these findings suggest that vitamin D(3) has an antiviral activity which is mediated by its active metabolite. This antiviral activity involves the induction of the interferon signaling pathway, resulting in expression of interferon-β and the interferon-stimulated gene, MxA. Intriguingly, HCV infection increased calcitriol production by inhibiting CYP24A1 induction, the enzyme responsible for the first step in calcitriol catabolism. Importantly, the combination of vitamin D(3) or calcitriol and interferon-α synergistically inhibited viral production.
  
  
  CONCLUSIONS
  This study demonstrates for the first time a direct antiviral effect of vitamin D in an in vitro infectious virus production system. It proposes an interplay between the hepatic vitamin D endocrine system and HCV, suggesting that vitamin D has a role as a natural antiviral mediator. Importantly, our study implies that vitamin D might have an interferon-sparing effect, thus improving antiviral treatment of HCV-infected patients.
authors.affiliation: Molecular Hepatology Research Laboratory, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Meital
authors.initials: M
authors.lastname: Gal-Tanamy
authors.forename: Larisa
authors.initials: L
authors.lastname: Bachmetov
authors.forename: Amiram
authors.initials: A
authors.lastname: Ravid
authors.forename: Ruth
authors.initials: R
authors.lastname: Koren
authors.forename: Arie
authors.initials: A
authors.lastname: Erman
authors.forename: Ran
authors.initials: R
authors.lastname: Tur-Kaspa
authors.forename: Romy
authors.initials: R
authors.lastname: Zemel
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology; D002117:Calcitriol / Q000096:biosynthesis* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D002762:Cholecalciferol / Q000493:pharmacokinetics*; D004357:Drug Synergism; D016174:Hepacivirus / Q000187:drug effects* / Q000254:growth & development; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D008113:Liver Neoplasms; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D065668:Vitamin D3 24-Hydroxylase; D014815:Vitamins / Q000493:pharmacokinetics
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D014815:Vitamins; D002762:Cholecalciferol; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol