TY - JOUR
T1 - Naturally occurring C-terminally truncated STAT5 is a negative regulator of HIV-1 expression
AU - Crotti, Andrea
AU - Lusic, Marina
AU - Lupo, Rossella
AU - Lievens, Patricia M J
AU - Liboi, Elio
AU - Della Chiara, Giulia
AU - Tinelli, Marco
AU - Lazzarin, Adriano
AU - Patterson, Bruce K.
AU - Giacca, Mauro
AU - Bovolenta, Chiara
AU - Poli, Guido
PY - 2007/6/15
Y1 - 2007/6/15
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2006-08-042556
DO - 10.1182/blood-2006-08-042556
M3 - Article
C2 - 17332243
AN - SCOPUS:34250023195
VL - 109
SP - 5380
EP - 5389
JO - Blood
JF - Blood
SN - 0006-4971
IS - 12
ER -