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Inhibition of Epstein-Barr Virus Lytic Reactivation by the Atypical Antipsychotic Drug Clozapine

Department of Chemistry & Biochemistry, University of Wisconsin-La Crosse, 1725 State St., La Crosse, WI 54601, USA
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Author to whom correspondence should be addressed.
Viruses 2019, 11(5), 450; https://doi.org/10.3390/v11050450
Received: 2 April 2019 / Revised: 9 May 2019 / Accepted: 15 May 2019 / Published: 17 May 2019
(This article belongs to the Special Issue Antiviral Agents)
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PDF [1883 KB, uploaded 17 May 2019]
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Abstract

Epstein–Barr virus (EBV), a member of the Herpesviridae family, maintains a lifelong latent infection in human B cells. Switching from the latent to the lytic phase of its lifecycle allows the virus to replicate and spread. The viral lytic cycle is induced in infected cultured cells by drugs such as sodium butyrate and azacytidine. Lytic reactivation can be inhibited by natural products and pharmaceuticals. The anticonvulsant drugs valproic acid and valpromide inhibit EBV in Burkitt lymphoma cells. Therefore, other drugs that treat neurological and psychological disorders were investigated for effects on EBV lytic reactivation. Clozapine, an atypical antipsychotic drug used to treat schizophrenia and bipolar disorder, was found to inhibit the reactivation of the EBV lytic cycle. Levels of the viral lytic genes BZLF1, BRLF1, and BMLF1 were decreased by treatment with clozapine in induced Burkitt lymphoma cells. The effects on viral gene expression were dependent on the dose of clozapine, yet cells were viable at an inhibitory concentration of clozapine. One metabolite of clozapine—desmethylclozapine—also inhibited EBV lytic reactivation, while another metabolite—clozapine-N-oxide—had no effect. These drugs may be used to study cellular pathways that control the viral lytic switch in order to develop treatments for diseases caused by EBV. View Full-Text
Keywords: Epstein–Barr virus; herpes viruses; lytic gene expression; Burkitt lymphoma cells; clozapine; antipsychotic drug; antiviral drug Epstein–Barr virus; herpes viruses; lytic gene expression; Burkitt lymphoma cells; clozapine; antipsychotic drug; antiviral drug
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Anderson, A.G.; Gaffy, C.B.; Weseli, J.R.; Gorres, K.L. Inhibition of Epstein-Barr Virus Lytic Reactivation by the Atypical Antipsychotic Drug Clozapine. Viruses 2019, 11, 450.

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