GENOMIC ORGANIZATION AND FUNCTIONAL-CHARACTERIZATION OF THE CHEMOKINERECEPTOR CXCR4, A MAJOR ENTRY CORECEPTOR FOR HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1

CXCR4 is both a chemokine receptor and entry co-preceptor for T cell l ime-adapted human immunodeficiency virus type 1. The genomic organizat ion and promoter function for the entire transcription unit of CXCR4 w ere determined, The gene contains 2 exons of 103 and 1563 base pairs ( bp) interrupted by a 2132-bp intron precisely between codons 5 and 6 o f the coding sequences. a transcription start site was identified 88 b p upstream of the initiation codon, and a polyadenylate addition sits was identified 22 bp 3' to a polyadenylation signal, Transient express ion assays defined a minimal promoter at positions -114 to +43 relativ e to the transcription start site. This region contains a TATA box, a nuclear respiratory factor-1 (NRF-1) site, and two GC boxes. Specific factor binding to the NRF-1 site and GC boxes were demonstrated by gel mobility shifts and DNase I footprinting. Site-directed mutagenesis s howed that the NRF-1 site is crucial for promoter activity providing t he first evidence for the regulation of a signal transduction gene by NRF-1. Sequences between -691 and -191 repress CXCR4 promoter activity . Further study of these regulatory elements will be important to unde rstanding how CXCR4 functions as both a chemokine receptor and human i mmunodeficiency virus type 1 entry co-receptor.