title: Naturally occurring C-terminally truncated STAT5 is a negative regulator of HIV-1 expression.
abstract: CD4(+) cells of most individuals infected with HIV-1 harbor a C-terminally truncated and constitutively activated form of signal transducer and activator of transcription-5 (STAT5 Delta). We report that the chronically HIV-infected U1 cell line expresses STAT5 Delta but not full-length STAT5. Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation of U1 cells promoted early activation of STAT5 Delta and of extracellular signal regulated kinases (ERKs), followed by later activation of activator protein 1 (AP-1) and HIV expression. Inhibition of ERK/AP-1 by PD98,059 abolished, whereas either tyrphostin AG490 or a STAT5 small interfering RNA (siRNA) enhanced, virion production in GM-CSF-stimulated U1 cells. Chromatin immunoprecipitation demonstrated the induction of STAT5 Delta binding to STAT consensus sequences in the HIV-1 promoter together with a decreased recruitment of RNA polymerase II after 1 hour of GM-CSF stimulation of U1 cells. Down-regulation of STAT5 Delta by siRNA resulted in the up-regulation of both HIV-1 gag-pol RNA and p24 Gag antigen expression in CD8-depleted leukocytes of several HIV-positive individuals cultivated ex vivo in the presence of interleukin-2 but not of interleukin-7. Thus, the constitutively activated STAT5 Delta present in the leukocytes of most HIV-positive individuals acts as a negative regulator of HIV expression.
authors.affiliation: AIDS Immunopathogenesis Unit and the Division of Infectious Diseases, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Crotti
authors.forename: Marina
authors.initials: M
authors.lastname: Lusic
authors.forename: Rossella
authors.initials: R
authors.lastname: Lupo
authors.forename: Patricia M J
authors.initials: PM
authors.lastname: Lievens
authors.forename: Elio
authors.initials: E
authors.lastname: Liboi
authors.forename: Giulia
authors.initials: G
authors.lastname: Della Chiara
authors.forename: Marco
authors.initials: M
authors.lastname: Tinelli
authors.forename: Adriano
authors.initials: A
authors.lastname: Lazzarin
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Patterson
authors.forename: Mauro
authors.initials: M
authors.lastname: Giacca
authors.forename: Chiara
authors.initials: C
authors.lastname: Bovolenta
authors.forename: Guido
authors.initials: G
authors.lastname: Poli
mesh_terms: D002460:Cell Line; D002478:Cells, Cultured; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D015658:HIV Infections; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D007962:Leukocytes / Q000821:virology; D050799:STAT5 Transcription Factor / Q000276:immunology*; D014779:Virus Replication
chemical_list: D050799:STAT5 Transcription Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor