CCAAT-enhancer-binding protein beta (C/EBP beta) activates CCR5 promoter: Increased C/EBP beta and CCR5 in T lymphocytes from HIV-1-infected individuals

C/EBP beta is a member of a family of leucine zipper transcription factors that are involved in regulating the expression of several cytokines, includ ing IL-1, IL-6, IL-8, TNF, and macrophage-inflammatory protein-1 alpha. We identified multiple C/EBP beta binding sites within the gene for CCR5, sugg esting that C/EBP beta may be involved in its regulation. Transient transfe ction experiments in both myeloid and lymphoid cells showed an increase in CCR5 promoter-driven green fluorescent protein production in the presence o f C/EBP beta. Deletion analysis identified two C/EBP beta -responsive regio ns in the CCR5 gene, one in the promoter region and one at the 3' part of t he intron. We provide evidence that, in myeloid cells (U937), C/EBP beta in dependently activates CCR5 expression through sites located either in the p romoter region or in the intron of the CCR5 gene. In contrast, in lymphoid cells (jurkat) the presence of the intronic cis-regulatory regions is requi red for C/EBP beta -mediated activation. In agreement with the functional d ata, EMSA demonstrated that in both myeloid and lymphoid cells C/EBP beta b inds specifically to sites present in the intron, whereas interaction with the sites located in the promoter was cell type specific and was detected o nly in myeloid cells. Analysis of C/EBP beta in primary PBMCs obtained from HIV-1-infected individuals revealed a significant increase in C/EBP beta e xpression. The enhanced C/EBP beta activity correlated with a higher freque ncy of circulating CCR5(+) lymphocytes in AIDS patients and with a decline in CD4 lymphocyte numbers. Taken together, these results suggest that C/FBP beta is an important regulator of CCR5 expression and may play a relevant role in the pathogenesis of HIV disease.