title: Niclosamide inhibits lytic replication of Epstein-Barr virus by disrupting mTOR activation.
abstract: Infection with the oncogenic γ-herpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) cause several severe malignancies in humans. Inhibition of the lytic replication of EBV and KSHV eliminates the reservoir of persistent infection and transmission, consequently preventing the occurrence of diseases from the sources of infection. Antiviral drugs are limited in controlling these viral infectious diseases. Here, we demonstrate that niclosamide, an old anthelmintic drug, inhibits mTOR activation during EBV lytic replication. Consequently, niclosamide effectively suppresses EBV lytic gene expression, viral DNA lytic replication and virion production in EBV-infected lymphoma cells and epithelial cells. Niclosamide exhibits cytotoxicity toward lymphoma cells and induces irreversible cell cycle arrest in lytically EBV-infected cells. The ectopic overexpression of mTOR reverses the inhibition of niclosamide in EBV lytic replication. Similarly, niclosamide inhibits KSHV lytic replication. Thus, we conclude that niclosamide is a promising candidate for chemotherapy against the acute occurrence and transmission of infectious diseases of oncogenic γ-herpesviruses.
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Huang
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Mengtian
authors.initials: M
authors.lastname: Yang
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China. Electronic address: lixjuan3@mail.sysu.edu.cn.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Li
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, China. Electronic address: kuangersh@mail.sysu.edu.cn.
authors.forename: Ersheng
authors.initials: E
authors.lastname: Kuang
mesh_terms: D045744:Cell Line, Tumor; D004261:DNA Replication / Q000187:drug effects*; D004847:Epithelial Cells / Q000821:virology; D020031:Epstein-Barr Virus Infections / Q000635:transmission / Q000821:virology; D004854:Herpesvirus 4, Human / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D009534:Niclosamide / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014771:Virion / Q000187:drug effects; D014775:Virus Activation / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D014764:Viral Proteins; D009534:Niclosamide; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Epstein-Barr virus; Kaposi's sarcoma-associated herpesvirus; Lytic replication; Niclosamide; mTOR