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

Overview

Journal Viruses

Publisher MDPI

Specialty Microbiology

Date 2019 May 22

PMID 31108875

Citations 9

Authors

Abbie G Anderson

Cullen B Gaffy

Joshua R Weseli

Kelly L Gorres

Affiliations

Soon will be listed here.

Abstract

Epstein-Barr virus (EBV), a member of the 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.

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References

Serafeim A, Grafton G, Chamba A, Gregory C, Blakely R, Bowery N . 5-Hydroxytryptamine drives apoptosis in biopsylike Burkitt lymphoma cells: reversal by selective serotonin reuptake inhibitors. Blood. 2002; 99(7):2545-53. DOI: 10.1182/blood.v99.7.2545. View

Baum S, Ashok A, Gee G, Dimitrova S, Querbes W, Jordan J . Early events in the life cycle of JC virus as potential therapeutic targets for the treatment of progressive multifocal leukoencephalopathy. J Neurovirol. 2003; 9 Suppl 1:32-7. DOI: 10.1080/13550280390195342. View

Sur C, Mallorga P, Wittmann M, Jacobson M, Pascarella D, Williams J . N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity. Proc Natl Acad Sci U S A. 2003; 100(23):13674-9. PMC: 263872. DOI: 10.1073/pnas.1835612100. View

Meltzer H . What's atypical about atypical antipsychotic drugs?. Curr Opin Pharmacol. 2004; 4(1):53-7. DOI: 10.1016/j.coph.2003.09.010. View

Miller G, El-Guindy A, Countryman J, Ye J, Gradoville L . Lytic cycle switches of oncogenic human gammaherpesviruses. Adv Cancer Res. 2007; 97:81-109. DOI: 10.1016/S0065-230X(06)97004-3. View

Mauri M, Volonteri L, Colasanti A, Fiorentini A, De Gaspari I, Bareggi S . Clinical pharmacokinetics of atypical antipsychotics: a critical review of the relationship between plasma concentrations and clinical response. Clin Pharmacokinet. 2007; 46(5):359-88. DOI: 10.2165/00003088-200746050-00001. View

Heiser P, Enning F, Krieg J, Vedder H . Effects of haloperidol, clozapine and olanzapine on the survival of human neuronal and immune cells in vitro. J Psychopharmacol. 2007; 21(8):851-6. DOI: 10.1177/0269881107077221. View

Kuroki T, Nagao N, Nakahara T . Neuropharmacology of second-generation antipsychotic drugs: a validity of the serotonin-dopamine hypothesis. Prog Brain Res. 2008; 172:199-212. DOI: 10.1016/S0079-6123(08)00910-2. View

Countryman J, Gradoville L, Bhaduri-McIntosh S, Ye J, Heston L, Himmelfarb S . Stimulus duration and response time independently influence the kinetics of lytic cycle reactivation of Epstein-Barr virus. J Virol. 2009; 83(20):10694-709. PMC: 2753116. DOI: 10.1128/JVI.01172-09. View

10.

Monti B, Polazzi E, Contestabile A . Biochemical, molecular and epigenetic mechanisms of valproic acid neuroprotection. Curr Mol Pharmacol. 2009; 2(1):95-109. DOI: 10.2174/1874467210902010095. View

11.

Rinaldi A, Chiaravalli A, Mian M, Zucca E, Tibiletti M, Capella C . Serotonin receptor 3A expression in normal and neoplastic B cells. Pathobiology. 2010; 77(3):129-35. DOI: 10.1159/000292646. View

12.

Daigle D, Gradoville L, Tuck D, Schulz V, Wangondu R, Ye J . Valproic acid antagonizes the capacity of other histone deacetylase inhibitors to activate the Epstein-barr virus lytic cycle. J Virol. 2011; 85(11):5628-43. PMC: 3094991. DOI: 10.1128/JVI.02659-10. View

13.

Meltzer H, Massey B . The role of serotonin receptors in the action of atypical antipsychotic drugs. Curr Opin Pharmacol. 2011; 11(1):59-67. DOI: 10.1016/j.coph.2011.02.007. View

14.

Ghosh A, Chakraborty K, Mattoo S . Newer molecules in the treatment of schizophrenia: A clinical update. Indian J Pharmacol. 2011; 43(2):105-12. PMC: 3081445. DOI: 10.4103/0253-7613.77334. View

15.

Heusler P, Bruins Slot L, Tourette A, Tardif S, Cussac D . The clozapine metabolite N-desmethylclozapine displays variable activity in diverse functional assays at human dopamine D₂ and serotonin 5-HT₁A receptors. Eur J Pharmacol. 2011; 669(1-3):51-8. DOI: 10.1016/j.ejphar.2011.07.031. View

16.

Luka J, Kallin B, Klein G . Induction of the Epstein-Barr virus (EBV) cycle in latently infected cells by n-butyrate. Virology. 1979; 94(1):228-31. DOI: 10.1016/0042-6822(79)90455-0. View

17.

Diem O, Schaffner M, Seifarth W, Leib-Mosch C . Influence of antipsychotic drugs on human endogenous retrovirus (HERV) transcription in brain cells. PLoS One. 2012; 7(1):e30054. PMC: 3256206. DOI: 10.1371/journal.pone.0030054. View

18.

Chen M, Tsai T, Wang L, Lin Y, Tsai Y, Lee M . Clozapine inhibits Th1 cell differentiation and causes the suppression of IFN-γ production in peripheral blood mononuclear cells. Immunopharmacol Immunotoxicol. 2012; 34(4):686-94. DOI: 10.3109/08923973.2011.651535. View

19.

Stark A, Scott J . A review of the use of clozapine levels to guide treatment and determine cause of death. Aust N Z J Psychiatry. 2012; 46(9):816-25. DOI: 10.1177/0004867412438871. View

20.

Roge R, Moller B, Andersen C, Correll C, Nielsen J . Immunomodulatory effects of clozapine and their clinical implications: what have we learned so far?. Schizophr Res. 2012; 140(1-3):204-13. DOI: 10.1016/j.schres.2012.06.020. View