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.
Highlights
Epstein–Barr virus (EBV) is a member of the Herpesviridae family and causes infectious mononucleosis
We demonstrate here that clozapine and one of its metabolites inhibit the induction of EBV lytic cycle gene expression
We investigated the response of EBV to the atypical antipsychotic drug clozapine
Summary
Epstein–Barr virus (EBV) is a member of the Herpesviridae family and causes infectious mononucleosis. EBV was the first virus discovered to cause cancer in humans. EBV is associated with Burkitt lymphoma, Hodgkin lymphoma, gastric carcinoma, nasopharyngeal carcinoma, and post-transplant lymphoproliferative disorder. After infection with EBV, the virus maintains a lifelong latent infection within the host. The expression of a few viral genes during the latent phase allows the virus to persist. The viral life cycle alternates between two phases: the latent and the lytic phases. During the lytic phase the virus replicates and spreads among cells and hosts
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