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Blood, 15 June 2007, Vol. 109, No. 12, pp. 5380-5389.
Prepublished online as a Blood First Edition Paper on March 1, 2007; DOI 10.1182/blood-2006-08-042556.
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IMMUNOBIOLOGY
Naturally occurring C-terminally truncated STAT5 is a negative regulator of HIV-1 expression
Andrea Crotti1,
Marina Lusic2,
Rossella Lupo3,
Patricia M. J. Lievens4,
Elio Liboi4,
Giulia Della Chiara1,
Marco Tinelli5,
Adriano Lazzarin1,6,
Bruce K. Patterson7,
Mauro Giacca2,
Chiara Bovolenta3, and
Guido Poli1,6
1 AIDS Immunopathogenesis Unit and the Division of Infectious Diseases, San Raffaele Scientific Institute, Milano, Italy;
2 International Centre for Genetic Engineering and Biotechnology, Trieste, Italy;
3 Molmed, Milano, Italy;
4 Division of Biochemistry, Department of Morphological and Biomedical Sciences, University of Verona Medical School, Verona, Italy;
5 Division of Infectious and Tropical Diseases, Hospital of Lodi, Lodi, Italy;
6 Vita-Salute San Raffaele University, School of Medicine, Milano, Italy;
7 Department of Pathology and Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA
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 ). We report that the chronically HIV-infected U1 cell line expresses STAT5 but not full-length STAT5. Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation of U1 cells promoted early activation of STAT5 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 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 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 present in the leukocytes of most HIV-positive individuals acts as a negative regulator of HIV expression.
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