In:
Blood, American Society of Hematology, Vol. 109, No. 12 ( 2007-06-15), p. 5380-5389
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.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood-2006-08-042556
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2007
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
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