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

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.

Challenges in Prescribing Clozapine in the Era of COVID-19: A Review Focused on Immunological Implications

“…On the other hand, several psychoactive agents, including clozapine, have antiviral effects [ 57 ]. Clozapine inhibited the reactivation of the Epstein–Barr virus lytic cycle in induced Burkitt lymphoma cells and some clozapine metabolites were found to suppress the replication of dengue virus, respiratory syncytial virus, rotavirus, and human immunodeficiency virus [ 58 ].…”

Screened antipsychotic drugs inhibit SARS-CoV-2 binding with ACE2 in vitro

“…Epstein–Barr virus (EBV) maintains a lifelong latent presence in human B cells and switching from the latent to the lytic cycle in infected cultured cells allows EBV to replicate and spread. Clozapine was found to inhibit reactivation of the EBV lytic cycle by decreasing the levels of the viral lytic genes BZLF1, BRLF1, and BMLF1 [ 18 ]. Thioridazine, another antipsychotic drug, was confirmed to inhibit the cell entry of EBOV by directly interacting with the glycoprotein of EBOV.…”

Valproic Acid and Its Amidic Derivatives as New Antivirals against Alphaherpesviruses

“…Moreover, some studies demonstrated that VPA inhibits the reactivation of Epstein-Barr virus (EBV) lytic cycle in vitro due to VPA's HDAC inhibitory activity. However, despite the fact that VPD does not have this HDAC inhibitory property, it still inhibits reactivation of the EBV lytic cycle [70,71]. Furthermore, a recent study has shown that VPA could also have a potential antiviral effect against RNA virus SARS-CoV-2, as it reduces the number of angiotensin-converting enzyme 2 (ACE-2) in endothelial cells, the main cellular receptor that this coronavirus uses to enter the cell [72].…”