title: Early events in the life cycle of JC virus as potential therapeutic targets for the treatment of progressive multifocal leukoencephalopathy.
abstract: The human polyomavirus, JC virus (JCV), is the etiological agent of progressive multifocal leukoencephalopathy (PML). PML occurs almost exclusively in the setting of severe and prolonged immunosuppression and it remains an important and life-threatening complication in the acquired immunodeficiency syndrome (AIDS) population. Several drugs that target DNA replication have shown efficacy at inhibiting JCV replication in vitro but none to date have shown in vivo efficacy. The authors' laboratory has been studying early events that contribute to infection of susceptible cells by JCV. They previously demonstrated that infection of glial cells by JCV requires clathrin-dependent endocytosis and that this early step in the viral life cycle can be blocked by the antipsychotic drug, chlorpromazine. As chlorpromazine is associated with the development of extrapyramidal symptoms that may be heightened in AIDS patients, the authors sought to test the atypical antipsychotic, clozapine, for antiviral activity against JCV. In this report, the authors show that clozapine is as effective as chlorpromazine at inhibiting infection. They further demonstrate that low-dose combinations of both drugs synergistically inhibit infection.
authors.affiliation: Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island 02912, USA.
authors.forename: S
authors.initials: S
authors.lastname: Baum
authors.forename: A
authors.initials: A
authors.lastname: Ashok
authors.forename: G
authors.initials: G
authors.lastname: Gee
authors.forename: S
authors.initials: S
authors.lastname: Dimitrova
authors.forename: W
authors.initials: W
authors.lastname: Querbes
authors.forename: J
authors.initials: J
authors.lastname: Jordan
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Atwood
mesh_terms: D014150:Antipsychotic Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002746:Chlorpromazine / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D007577:JC Virus / Q000187:drug effects* / Q000254:growth & development; D007968:Leukoencephalopathy, Progressive Multifocal / Q000188:drug therapy* / Q000821:virology; D009457:Neuroglia / Q000166:cytology / Q000821:virology
chemical_list: D014150:Antipsychotic Agents; D000998:Antiviral Agents; D003024:Clozapine; D002746:Chlorpromazine