It has recently been shown that hepatitis B virus (HBV) contains a transcriptional enhancer element. In order to determine whether this enhancer responds to

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,

These findings suggest an association between the genetic ability to produce low levels of IFN-gamma and the susceptibility to develop chronic HBV infection.

Phytochemicals exert antiviral activity and may play a potential therapeutic role in hepatitis C virus (HCV) infection. In this work, we aimed to isolate NS3 inhibitors from traditional Indian medicinal plants that were found, in our earlier study, to inhibit HCV NS3 protease activity and to evaluate their potential to inhibit HCV replication. A potent inhibitory effect of NS3 catalytic activity was obtained with Embelia ribes plant extracts. Quercetin, a ubiquitous plant flavonoid, was identified as the active substance in the fractioned extract. It was found to inhibit NS3 activity in a specific dose-dependent manner in an in vitro catalysis assay. Quercetin inhibited HCV RNA replication as analysed in the subgenomic HCV RNA replicon system. It also inhibited HCV infectious virus production in the HCV infectious cell culture system (HCVcc), as analysed by the focus-forming unit reduction assay and HCV RNA real-time PCR. The inhibitory effect of quercetin was also obtained when using a model system in which NS3 engineered substrates were introduced in NS3-expressing cells, providing evidence that inhibition in vivo could be directed to the NS3 and do not involve other HCV proteins. Our work demonstrates that quercetin has a direct inhibitory effect on the HCV NS3 protease. These results point to the potential of quercetin as a natural nontoxic anti-HCV agent reducing viral production by inhibiting both NS3 and heat shock proteins essential for HCV replication.