Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
Hepatology. 2012 Oct;56(4):1231-9. doi: 10.1002/hep.25763.
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.
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) .
由于目前针对丙型肝炎病毒（HCV）感染的干扰素（IFN）治疗存在治疗局限性和副作用，因此需要更有效的治疗策略。最近的研究表明，维生素 D 的补充通过基于 IFN 的治疗显著提高了持续病毒应答率。然而，维生素 D 对 HCV 的作用机制及其有效分子形式尚未完全阐明。为了解决这些问题，我们在存在或不存在维生素 D（3）或其代谢物的情况下，用细胞培养生成的 HCV 感染 HuH-7 细胞。令我们惊讶的是，25-羟维生素 D（3）[25（OH）D（3）]，而不是维生素 D（3）或 1,25-二羟维生素 D（3），以浓度依赖的方式降低了 HCV 核心抗原的细胞内外水平。用 CD81 阴性细胞系进行的单周期病毒产生测定显示，25（OH）D（3）的抑制作用发生在感染性病毒组装水平，而不是进入或复制水平。长期 25（OH）D（3）处理会产生对 25（OH）D（3）产生获得性耐药的 HCV 突变体，这种突变导致非结构区域 3 解旋酶结构域中的 N1279Y 取代，是耐药的原因。
25（OH）D（3）是一种针对感染性病毒颗粒组装步骤的新型抗 HCV 药物。这一发现为通过维生素 D（3）和 IFN 的联合治疗提高抗 HCV 治疗的疗效提供了深入了解。我们的结果还表明，在肝功能障碍和生成 25（OH）D（3）的酶活性降低的患者中，25（OH）D（3），而不是维生素 D（3），是更好的治疗选择。
