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Blood, 15 November 2005, Vol. 106, No. 10, pp. 3440-3448.
Prepublished online as a Blood First Edition Paper on August 9, 2005; DOI 10.1182/blood-2005-03-0857.
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Submitted March 1, 2005
Accepted June 30, 2005
The transcription factor GATA-1 potently represses the expression of the HIV-1 co-receptor CCR5 in human T cells and dendritic cells
Mark S Sundrud, Scott E VanCompernolle, Karla A Eger, Tullia C Bruno, Arun Subramaniam, Srinivas Mummidi, Sunil K Ahuja, and Derya Unutmaz*
Department of Microbiology and Immunology, Vanderbilt University Medical School, Nashville, TN, USA
Department of Internal Medicine, Sanofi Aventis Pharmaceuticals, Bridgewater, NJ, USA
Veterans Administration Center for AIDS and HIV infection, South Texas Veterans Health Care System, and Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
* Corresponding author; email: derya.unutmaz{at}vanderbilt.edu.
CCR5 is the major HIV-1 co-receptor and its expression levels are a critical determinant of HIV-1 infection. However, the molecular mechanisms of CCR5 regulation in primary targets of HIV-1 remain unknown. Despite binding to conserved DNA-elements, we show that the transcription factors GATA-1 and GATA-3 differentially suppress the expression of CCR5 in stem cell-derived dendritic cells and primary human T cell subsets. In addition, GATA-1 expression was also more potent than GATA-3 in suppressing Th1 associated genes, IFN and CXCR3. GATA-1, but not GATA-3, potently suppressed CCR5 transcription, thereby rendering human T cells resistant to CCR5-tropic HIV-1 infection. However, GATA-1 also substituted for GATA-3 in its canonical role of programming Th2 gene expression. These findings provide insight into GATA-3-mediated gene regulation during T cell differentiation. Importantly, decoding the mechanisms of GATA-1-mediated repression of CCR5 may offer an opportunity to develop novel approaches to inhibit CCR5 expression in T cells.

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