CCAAT-Enhancer-Binding Protein β (C/EBPβ) Activates CCR5 Promoter: Increased C/EBPβ and CCR5 in T Lymphocytes from HIV-1-Infected Individuals

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Abstract
C/EBPβ is a member of a family of leucine zipper transcription factors that are involved in regulating the expression of several cytokines, including IL-1, IL-6, IL-8, TNF, and macrophage-inflammatory protein-1α. We identified multiple C/EBPβ binding sites within the gene for CCR5, suggesting that C/EBPβ may be involved in its regulation. Transient transfection experiments in both myeloid and lymphoid cells showed an increase in CCR5 promoter-driven green fluorescent protein production in the presence of C/EBPβ. Deletion analysis identified two C/EBPβ-responsive regions in the CCR5 gene, one in the promoter region and one at the 3′ part of the intron. We provide evidence that, in myeloid cells (U937), C/EBPβ independently activates CCR5 expression through sites located either in the promoter region or in the intron of the CCR5 gene. In contrast, in lymphoid cells (Jurkat) the presence of the intronic cis-regulatory regions is required for C/EBPβ-mediated activation. In agreement with the functional data, EMSA demonstrated that in both myeloid and lymphoid cells C/EBPβ binds specifically to sites present in the intron, whereas interaction with the sites located in the promoter was cell type specific and was detected only in myeloid cells. Analysis of C/EBPβ in primary PBMCs obtained from HIV-1-infected individuals revealed a significant increase in C/EBPβ expression. The enhanced C/EBPβ activity correlated with a higher frequency of circulating CCR5+ lymphocytes in AIDS patients and with a decline in CD4 lymphocyte numbers. Taken together, these results suggest that C/EBPβ is an important regulator of CCR5 expression and may play a relevant role in the pathogenesis of HIV disease.