title: Caspase inhibition activates HIV in latently infected cells. Role of tumor necrosis factor receptor 1 and CD95.
abstract: Stimulation of tumor necrosis factor receptor 1 (TNF-R1) triggers both caspase-dependent and caspase-independent signaling activities. The caspase-dependent signaling pathway induces apoptotic cell death in susceptible cells, whereas the caspase-independent signaling cascade leads to activation of nuclear factor kappa B and induces antiapoptotic signaling activities. Stimulation of nuclear factor kappa B via TNF-R1 is known to activate human immunodeficiency virus (HIV) replication in infected cells. Here we show that the broad range caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (ZVAD) activates HIV replication in the chronically infected T-cell line ACH-2. Virus activation was caused by a sensitization of TNF-R1 toward endogenously produced tumor necrosis factor alpha (TNF-alpha). Neutralizing anti-TNF-alpha antibodies completely abolished the virus-inducing activity of ZVAD. Treatment of cells with TNF-alpha in the presence of ZVAD caused increased expression of TNF-alpha and induced enhanced virus replication. Activation of CD95, another member of the TNF receptor family, similarly triggered HIV replication, which was further enhanced in the presence of ZVAD. Our data show that caspase inhibitors sensitize both CD95 and TNF-R1 to mediate activation of HIV in latently infected cells. Activation of HIV replication in latent virus reservoirs is currently discussed as a therapeutic strategy to achieve eradication of HIV in patients treated with antiretroviral therapy. Our results point to a novel role for caspase inhibitors as activators of virus replication in vivo.
authors.affiliation: Institute for Virology and Immunobiology, Julius-Maximilians-Universität, 97078 Würzburg, Germany. scheller@vim.uni-wuerzburg.de
authors.forename: Carsten
authors.initials: C
authors.lastname: Scheller
authors.forename: Sieghart
authors.initials: S
authors.lastname: Sopper
authors.forename: Peifeng
authors.initials: P
authors.lastname: Chen
authors.forename: Egbert
authors.initials: E
authors.lastname: Flory
authors.forename: Eleni
authors.initials: E
authors.lastname: Koutsilieri
authors.forename: Tomas
authors.initials: T
authors.lastname: Racek
authors.forename: Stephan
authors.initials: S
authors.lastname: Ludwig
authors.forename: Volker
authors.initials: V
authors.lastname: ter Meulen
authors.forename: Christian
authors.initials: C
authors.lastname: Jassoy
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000502:physiology*; D061945:Caspase Inhibitors; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D006678:HIV / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D013601:T-Lymphocytes; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D014775:Virus Activation / Q000187:drug effects*; D014779:Virus Replication / Q000502:physiology*; D019014:fas Receptor / Q000276:immunology / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor