All-trans retinoic acid for treatment of chronic hepatitis C

I Department of Internal Medicine, Johannes Gutenberg University Hospital, Mainz, Germany.
Liver international: official journal of the International Association for the Study of the Liver (Impact Factor: 4.85). 03/2008; 28(3):347-54. DOI: 10.1111/j.1478-3231.2007.01666.x
Source: PubMed


In vitro studies in the subgenomic hepatitis C virus (HCV) replicon system have identified all-trans retinoic acid (ATRA) as a potential therapeutic against hepatitis C. Thus, the antiviral potential of this drug should be assessed in vivo.
Twenty highly treatment experienced serotype 1 patients with non-response to conventional or pegylated interferon-alpha (Peg-/IFN-alpha) and ribavirin were randomly assigned to 12 weeks of monotherapy with ATRA (group A) or a combination of ATRA and PegIFN-alpha2a (group B). HCV RNA was assessed by bDNA assay and if negative by highly sensitive polymerase chain reaction.
During treatment, five of 10 patients in group A had a drop of viraemia >1log, while in group B after 8 weeks five of 10 dropped >2log, and three of 10 cleared HCV RNA from serum. Viraemia relapsed after treatment cessation. ATRA was rather well tolerated, with transient headache, dry skin and mucosa representing the most common side effects.
The viral load reduction under ATRA monotherapy, although limited and transient, supports the antiviral activity of ATRA. However, the rapid loss of HCV RNA in three of 10 previous non-responders under ATRA and PegIFN-alpha2a treatment demonstrates a strong additive or synergistic ATRA effect and calls for a controlled trial to assess the therapeutic potential of this drug.

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    • "Even when CH-C patients were treated with ATRA, the viral load dropped by 1–2 log units in 50% of the patients enrolled. In addition, when CH-C patients who showed no response to prior IFN/PEG-IFNα and ribavirin therapy were treated with a combination of ATRA and PEG-IFNα-2a, 30% of patients showed a significant viral reduction18. Recently, combined vitamin A and D deficiency prior to IFN-based therapy was shown to be a strong independent predictor of non-response to antiviral therapy19. "
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    • "Patients infected with Hepatitis C virus (HCV) and treated with 9-cis retinoic acid or ATRA in combination with pegylated IFNα have lower viral loads [69,70]. In contrast, supplements do not increase viral clearance in human papilloma virus (HPV)-infected women [71]. "
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    ABSTRACT: Measles-associated morbidity and mortality can be decreased in response to treatment with vitamin A. However, the mechanism underlying this beneficial effect is unknown. In this work, we investigate the molecular interaction between measles virus (MeV) and retinoids in vitro. Our first goal was to assess whether retinoids influence the in vitro replication of MeV. We found all-trans retinoic acid (ATRA), as well as other natural and synthetic retinoids, inhibited MeV replication in primary cells and a range of cell lines. This inhibitory effect was mediated through retinoid nuclear receptor signaling, and retinoic acid receptor alpha (RARalpha) in particular. Next, we sought to determine the role of type I interferon (IFN), since both MeV and retinoids can modulate IFN signaling. Type I IFN blocking antibodies abrogated the inhibitory effects of ATRA on MeV replication. IFN-stimulated genes (ISG) were upregulated by ATRA in MeV-infected cell cultures when compared to either treatment or infection alone. Using a transwell system, we determined that this increased gene expression occurred in initially uninfected bystander cells. The ATRA-treated bystander cells did not support substantial viral replication when subsequently challenged with MeV. Finally, we identified retinoid-induced gene I (RIG-I) as a link between the RARalpha - and IFN-dependent mechanism of MeV inhibition by retinoids. We found that RIG-I can be transcriptionally regulated by ATRA. Furthermore, RARalpha function was necessary for the induction of RIG-I by MeV and ATRA, and could bind to the RIG-I promoter. A retinoic acid response element (RARE) in the RIG-I promoter region was identified, and RIG-I promoter constructs were shown to produce luciferase in response to ATRA. Finally, we showed that functional RIG-I was necessary for ATRA to inhibit MeV replication. In summary, we have demonstrated that transcriptional regulation of RIG-I by ATRA through RARalphais required for inhibition of MeV. Furthermore, initially uninfected bystander cells upregulate their expression of ISGs, making them refractory to productive infection during subsequent rounds of viral replication. Therefore, we conclude that ATRA inhibits MeV replication through the RARalpha-dependent regulation of RIG-I and IFN signaling. Les taux de morbidité et de mortalité associés à la rougeole peuvent diminuer à la suite d'un traitement à la vitamine A ; or, le mécanisme à l'origine de cet effet bénéfique est encore inconnu. Par ce travail, nous avons voulu étudier les mécanismes résultant de l'interaction du virus de la rougeole (MeV) et des rétinoïdes in vitro. Nous avions d'abord comme objectif de déterminer si les rétinoïdes avaient un impact sur la réplication du MeV in vitro . Nous avons démontré que le ligand spécifique, l'acide tout-trans rétinoïque (ATRA), ainsi que d'autres rétinoïdes naturels et synthétiques inhibent la réplication du MeV chez des cellules primaires de même que chez un grand nombre de lignées cellulaires. Nous avons aussi démontré que la signalisation par les récepteurs nucléaires des rétinoïdes, en particulier le récepteur alpha de l'acide rétinoïque (RARalpha), était responsable de l'effet inhibiteur observé. Nous avons ensuite voulu déterminer le rôle de l'interféron de type I (IFN) puisqu'il est connu que MeV et les rétinoïdes peuvent moduler la signalisation de cet IFN de différentes façons. Nos recherches ont permis de démontrer que des anticorps bloquant la signalisation par l'IFN de type I renversent les effets inhibiteurs de l'ATRA sur la réplication du MeV, démontrant ainsi l'importance de la signalisation par cet IFN. En outre, l'ATRA augmente l'expression des gènes stimulés par l'IFN de type I (ISG) chez des cellules en culture infectées par le MeV comparativement aux cellules uniquement traitées à l'ATRA ou uniquement infectées par le MeV. L'utilisation d'un système Transwell a aussi permis de déterminer que l'augmentation de l'expression de ces gènes survient chez des cellules de voisinage non-infectées initialement par le MeV. Lorsque ces cellules, traitées à l'ATRA, étaient par la suite infectées au MeV, on n'y observait pas de réplication substantielle du virus. Finalement, nous avons identifié le gène I induit par les rétinoïdes (RIG-I) comme étant un lien entre les mécanismes d'inhibition du MeV par les rétinoïdes dépendant de RARalpha et de ceux dépendant de l'IFN de type I. On sait que RIG-I est impliqué dans la signalisation par l'IFN de type I et nous avons découvert que l'ATRA peut aussi réguler transcriptionnellement ce gène. Nous avons observé qu'un RARalpha fonctionnel est nécessaire à l'induction de RIG-I par le MeV et l'ATRA et qu'il peut se lier au promoteur de RIG-I. Nous avons ainsi identifié un élément de réponse de l'acide rétinoïque (RARE) dans la région du promoteur de RIG-I et des constructions de ce promoteur ont pu produire de la luciférase en réponse à l'ATRA. De plus, il est nécessaire d'avoir un gène RIG-I fonctionnel pour que l'ATRA puisse inhiber la réplication du MeV. En résumé, nous avons démontré que la régulation transcriptionnelle de RIG-I par ATRA par l'entremise de RARalpha est nécessaire pour inhiber la réplication du MeV. En outre, l'expression des ISG est augmentée chez les cellules de voisinage non-infectées, ce qui les rend réfractaires à une infection productive lors des périodes subséquentes de réplication virale. Donc, l'ATRA inhibe la réplication du MeV en régulant la signalisation par l'IFN de type I et RIG-I de façon dépendante de RARalpha.
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