Transcription factor GATA-1 potently represses the expression of the HIV-1 coreceptor CCR5 in human T cells and dendritic cells.
CC chemokine receptor 5 (CCR5) is the major HIV-1 coreceptor 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 binding protein 1 (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 T helper 1 (Th1)-associated genes, interferon-gamma (IFNgamma), and CXC chemokine receptor-3 (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 could also serve as a surrogate for GATA-3 in its canonic 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.
Sundrud
Mark S
MS
Department of Microbiology and Immunology, Vanderbilt University Medical School, Nashville, TN, USA.
Vancompernolle
Scott E
SE
Eger
Karla A
KA
Bruno
Tullia C
TC
Subramaniam
Arun
A
Mummidi
Srinivas
S
Ahuja
Sunil K
SK
Unutmaz
Derya
D
D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000821:virology; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000276:immunology*; D050990:GATA3 Transcription Factor; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D015658:HIV Infections / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D019713:Receptors, CCR5 / Q000235:genetics / Q000276:immunology*; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000276:immunology; D013234:Stem Cells / Q000166:cytology / Q000276:immunology* / Q000821:virology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000821:virology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology / Q000821:virology
C515187:CXCR3 protein, human; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D019713:Receptors, CCR5; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D007371:Interferon-gamma