Naturally occurring C-terminally truncated STAT5 is a negative regulator of HIV-1 expression

Andrea Crotti, Marina Lusic, Rossella Lupo, Patricia M J Lievens, Elio Liboi, Giulia Della Chiara, Marco Tinelli, Adriano Lazzarin, Bruce K. Patterson, Mauro Giacca, Chiara Bovolenta, Guido Poli

Research output: Contribution to journalArticle

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 (STAT5Δ). We report that the chronically HIV-infected U1 cell line expresses STAT5Δ but not full-length STAT5. Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation of U1 cells promoted early activation of STAT5Δ 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 STAT5Δ 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 STAT5Δ 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 STAT5Δ present in the leukocytes of most HIV-positive individuals acts as a negative regulator of HIV expression.

Original languageEnglish
Pages (from-to)5380-5389
Number of pages10
JournalBlood
Volume109
Issue number12
DOIs
Publication statusPublished - Jun 15 2007

ASJC Scopus subject areas

  • Hematology

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    Crotti, A., Lusic, M., Lupo, R., Lievens, P. M. J., Liboi, E., Della Chiara, G., Tinelli, M., Lazzarin, A., Patterson, B. K., Giacca, M., Bovolenta, C., & Poli, G. (2007). Naturally occurring C-terminally truncated STAT5 is a negative regulator of HIV-1 expression. Blood, 109(12), 5380-5389. https://doi.org/10.1182/blood-2006-08-042556