Tat predominantly associates with host promoter elements in HIV-1-infected T-cells - regulatory basis of transcriptional repression of c-Rel

Abstract

HIV-1 Tat is a multifunctional regulatory protein that, in addition to its primary function of transactivating viral transcription, also tends to modulate cellular gene expression, for which the molecular mechanism remains to be clarified. We have reported earlier nuclear factor kappa B (NFκB) enhancer binding activity of Tat and proposed this DNA binding activity as a possible molecular basis for Tat-mediated regulation of cellular gene expression in infected cells. In the present study, we analyzed the genome-wide occupancy of Tat protein on host cell chromatin in HIV-1-infected T-cells to investigate a potential role of Tat on cellular gene expression. The results obtained identify a spectrum of binding sites of Tat protein on the chromatin and reveal that Tat is also recruited on a number of cellular gene promoters in HIV-1-infected T-cells, indicating its possible involvement in the regulation of gene expression of such cellular genes. Tat was identified as a repressor of one such validated gene, c-Rel, because it downregulates the expression of c-Rel in both Tat expressing and HIV-1-infected T-cells. The results also show that Tat downregulates c-Rel promoter activity by interacting with specific NFκB sites on the c-Rel promoter, thus providing a molecular basis of Tat-mediated regulation of cellular gene expression. Thus, in the present study, we have not only identified recruitment sites of Tat on the chromatin in HIV-1-infected T-cells, but also report for the first time that c-Rel is downregulated in HIV-1-infected cells specifically by interaction of Tat with NFκB binding sites on the promoter.