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-b 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-a synergistically inhibited viral production. Conclusion: 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. (HEPATOLOGY 2011;54:1570-1579 H epatitis C virus (HCV) is a major cause of chronic hepatitis and the leading cause of endstage liver disease including liver cirrhosis and hepatocellular carcinoma. 1 It is a major global health challenge affecting an estimated 2.7 million people worldwide. 2 HCV is a small enveloped positive-strand RNA virus classified in the Hepacivirus genus within the Flaviviridae family. 3 It is characterized by a high genetic variability that reflects the low-fidelity rate together with the lack of a proofreading function of the viral RNA-dependant RNA polymerase. 1,3 HCV variability, which facilitates rapid development of antiviral resistance, provides a strong rationale for the development and implementation of antiviral combination therapies. 3 The best available HCV antiviral therapy is a combination of pegylated interferon-a (IFNa) and ribavirin-based therapy. 4 This treatment is aimed to obtain a sustained viral response (SVR), which is defined as undetectable serum HCV RNA 24 weeks posttherapy.Abbreviations: 1a-hydroxylase, 25-hydroxyvitamin-D 1a-hydroxylase; 1a,25(OH) 2D, 1a, 25(OH)D,

Suppression of Iron-Regulatory Hepcidin by Vitamin D

“…A similar mode of action has been reported for antibacterial effects of vitamin D in monocytes 11,12 and antiviral responses to vitamin D in human hepatocytes. 17 Intracrine responses to vitamin D appear to be exquisitely sensitive to the availability of substrate 25D, 11,12,18 suggesting that the hepcidin-ferroportin homeostasis system may be influenced by serum vitamin D (25D) status ( Figure 5). This hypothesis is supported by supplementation data from healthy volunteers showing that elevated serum concentrations of 25D (but not 1,25D) after a single oral dose of vitamin D 2 produced a 34% decrease in serum hepcidin concentrations that persisted for 72 hours (Figure 4).…”

A D-vitamin metabolizmusa humán hepatocellularis carcinomában és az azt körülvevő tumormentes májszövetben

“…Az irodalomból ismert, hogy hepatitis C-vírus-fertőzés esetén a májszövetben megemelkedik a helyi 1,25-dihidroxi-D 3 -vitamin-aktivitás az inaktiváló CYP24A1-expresszió csökkenésének hatására [56]. Egyik hepatitis C-vírus-fertőzött betegünk hepatocellularis carcinomájában sem volt kimutatható a CYP24A1 expressziója.…”

Is there an association between vitamin D and liver fibrosis in patients with chronic hepatitis C?

“…Vitamin D anti-inflammatory and modulating properties could impact on disease progression especially on HCV chronic liver disease (12) . Some authors observed that vitamin D might have an impact on other outcomes and in the response to the treatment of patients with chronic hepatitis C (8,18,21,26) .…”