Molecular Hepatology Research Laboratory, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Hepatology. 2011 Nov;54(5):1570-9. doi: 10.1002/hep.24575.
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.
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.
据报道，维生素 D 补充剂与抗病毒治疗丙型肝炎病毒（HCV）联合使用时，可提高持续病毒学应答的概率。我们的目的是确定维生素 D 在体外抑制 HCV 感染病毒产生的潜力，并探索抑制的机制。在这里，我们表明维生素 D（3）可显著抑制 Huh7.5 肝癌细胞中的 HCV 产生。这些细胞表达 CYP27B1，该基因编码负责合成维生素 D 激素活性代谢物骨化三醇的酶。用维生素 D（3）处理会导致骨化三醇的产生和骨化三醇靶基因 CYP24A1 的诱导，表明这些细胞含有完整的维生素 D 代谢和活性机制。值得注意的是，用骨化三醇处理会导致 HCV 抑制。总的来说，这些发现表明维生素 D（3）具有抗病毒活性，其由其活性代谢物介导。这种抗病毒活性涉及干扰素信号通路的诱导，导致干扰素-β和干扰素刺激基因 MxA 的表达。有趣的是，HCV 感染通过抑制 CYP24A1 诱导（负责骨化三醇分解代谢第一步的酶）来增加骨化三醇的产生。重要的是，维生素 D（3）或骨化三醇与干扰素-α的联合使用具有协同抑制病毒产生的作用。
本研究首次在体外感染病毒产生系统中证明了维生素 D 的直接抗病毒作用。它提出了肝维生素 D 内分泌系统与 HCV 之间的相互作用，表明维生素 D 作为一种天然抗病毒介质发挥作用。重要的是，我们的研究表明，维生素 D 可能具有干扰素节约作用，从而改善 HCV 感染患者的抗病毒治疗。
