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      Subversion of the Heme Oxygenase-1 Antiviral Activity by Zika Virus

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          Heme oxygenase-1 (HO-1), a rate-limiting enzyme involved in the degradation of heme, is induced in response to a wide range of stress conditions. HO-1 exerts antiviral activity against a broad range of viruses, including the Hepatitis C virus, the human immunodeficiency virus, and the dengue virus by inhibiting viral growth. It has been reported that HO-1 displays antiviral activity against the Zika virus (ZIKV) but the mechanisms of viral inhibition remain largely unknown. Using a ZIKV RNA replicon with the Green Fluorescent Protein (GFP) as a reporter protein, we were able to show that HO-1 expression resulted in the inhibition of viral RNA replication. Conversely, we observed a decrease in HO-1 expression in cells replicating the ZIKV RNA replicon. The study of human cells infected with ZIKV showed that the HO-1 expression level was significantly lower once viral replication was established, thereby limiting the antiviral effect of HO-1. Our work highlights the capacity of ZIKV to thwart the anti-replicative activity of HO-1 in human cells. Therefore, the modulation of HO-1 as a novel therapeutic strategy against ZIKV infection may display limited effect.

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          Most cited references 31

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          Guillain-Barré Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study.

          Between October, 2013, and April, 2014, French Polynesia experienced the largest Zika virus outbreak ever described at that time. During the same period, an increase in Guillain-Barré syndrome was reported, suggesting a possible association between Zika virus and Guillain-Barré syndrome. We aimed to assess the role of Zika virus and dengue virus infection in developing Guillain-Barré syndrome.
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            Zika virus: a previously slow pandemic spreads rapidly through the Americas.

            Zika virus (family Flaviviridae) is an emerging arbovirus. Spread by Aedes mosquitoes, it was first discovered in Uganda in 1947, and later in humans elsewhere in sub-Saharan Africa, arriving in south-east Asia at latest by the mid-twentieth century. In the twenty-first century, it spread across the Pacific islands reaching South America around 2014. Since then it has spread rapidly northwards reaching Mexico in November 2015. Its clinical profile is that of a dengue-like febrile illness, but associations with Guillain-Barré syndrome and microcephaly have appeared recently. The final geographical range and ultimate clinical impact of Zika virus are still a matter for speculation.
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              The South Pacific epidemic strain of Zika virus replicates efficiently in human epithelial A549 cells leading to IFN-β production and apoptosis induction.

              Zika virus (ZIKV) is an emerging flavivirus since the first epidemics in South Pacific in 2007. The recent finding that ZIKV is now circulating in Western Hemisphere and can be associated to severe human diseases, warrants the need for its study. Here we evaluate the susceptibility of human lung epithelial A549 cells to South Pacific epidemic strain of ZIKV isolated in 2013. We showed that ZIKV growth in A549 cells is greatly efficient. ZIKV infection resulted in the secretion of IFN-β followed by the expression of pro-inflammatory cytokines such as IL-1β, and transcriptional activity of IFIT genes. At the maximum of virus progeny production, ZIKV triggers mitochondrial apoptosis through activation of caspases-3 and -9. Whereas at early infection times, the rapid release of IFN-β which exerts an antiviral effect against ZIKV might delay apoptosis in infected cells.

                Author and article information

                20 December 2018
                January 2019
                : 11
                : 1
                [1 ]Université de La Réunion, INSERM UMR 1187, CNRS 9192, IRD 249 UMR PIMIT, Processus Infectieux en Milieu Insulaire Tropical, Plateforme CYROI, 2, rue Maxime Rivière, F-97490 Sainte-Clotilde, France; chaker.el-kalamouni@ (C.E.K.); etienne.frumence@ (E.F.); sandrabos.lab@ (S.B.); jonas97480@ (J.T.); wissalharrabi500@ (W.H.); dwilkin799@ (D.A.W.); gilles.gadea@ (G.G.); philippe.despres@ (P.D.)
                [2 ]Université de la Réunion, Inserm, UMR 1188 Diabète Athérothrombose Thérapies Réunion Océan Indien (DéTROI), F-97490 Sainte-Clotilde, France; brice.nativel@ (B.N.); olivier.meilhac@ (O.M.)
                [3 ]CHU de La Réunion, Saint-Denis de La Réunion, F-97400 Bellepierre, France
                Author notes
                [* ]Correspondence: pascale.krejbich@ (P.K.-T.); wildriss.viranaicken@ (W.V.); Tel.: +33-262938829 (P.K.-T. & W.V.)

                These authors contributed equally to this work.

                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (


                Microbiology & Virology

                antiviral, heme-oxygenase 1, zika virus, viral replication


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