Moriuchi M, Moriuchi H, Turner W, Fauci AS; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
A chemokine receptor CXCR4 (also designated fusin and LESTR) is a cofactor for fusion and entry of T cell-tropic strains of HIV-1. CXCR4 is expressed in various cell types; however, the mechanisms involved in the regulation of its expression remains unknown. In order to delineate these mechanisms, approximately 1.0 kb of DNA from the immediate 5" upstream region of CXCR4 was cloned, sequenced, and characterized. Transient expression assays using CXCR4 promoter/luciferase gene reporter constructs revealed that stimulation with PMA plus ionomycin upregulates the CXCR4 promoter activity in the A3.01 CD4+ T cell line, and that an approximately 0.2-kb fragment from -117 to +59 relative to the transcription start site is sufficient for the basal and induced activity. This fragment contains a consensus TATA box, a potential CRE site, two potential GC boxes, and a potential NRF-1 binding site, which were confirmed by gel mobility shift assays and footprinting analysis. Mutagenesis studies revealed that these cis-acting elements, especially an NRF-1 site, contribute markedly to the basal and induced activity of the CXCR4 promoter. Inducibility of the CXCR4 promoter activity by T cell activation and identification of cis-acting elements potentially involved in immune activation or in the expression of endogeneous cytokines suggest that overexpression of CXCR4 may lie one of the mechanisms whereby immune activation and/or perturbation of the cytokine network upregulate HIV expression and replication, and thus contribute to the progression of HIV disease.
Keywords: AEGIS, Promoter Regions (Genetics), HIV-1, Receptors, CXCR4, Virus Replication, Antigens, CD4, HIV Infections, Trans-Activators, DNA-Binding Proteins, T-Lymphocytes, Carrier Proteins, TATA Box, Luciferase, nuclear respiratory factor, analysis, genetics, virology, AIDS
