HIV-1 Tat represses transcription from the mannose receptor promoter

The mannose receptor is expressed on mature macrophages and immature dendri tic cells, and functions to mediate phagocytosis of pathogens and capture o f Ags for delivery to MHC class II-containing intracellular compartments. I t has been previously reported that HIV-1-infected macrophages have reduced functions associated with the mannose receptor, including impaired Pneumoc ystis carinii phagocytosis and mannosylated albumin uptake. Several HIV-1-d erived proteins including the Tat protein have been shown to transcriptiona lly repress host cell genes. The present study was undertaken to define the role of the HIV-1-derived protein Tat in HIV-mediated mannose receptor dow n-regulation. Cotransfection of the human macrophage cell line U937 with a Tat expression vector and a mannose receptor promoter-luciferase reporter c onstruct resulted in down-regulation of mannose receptor promoter activity. This repression was targeted to the basal promoter. Expression of either o ne- or two-exon Tat resulted in decreased promoter activity, The addition o f the transactivation response element (TAR) sequence enhanced the Tat-medi ated repression. Down-regulation was also seen when transfected cells were treated with exogenously added Tat protein, These results are consistent wi th a mechanism whereby Tar reduces mannose receptor promoter activity by in terfering with the host transcriptional initiation machinery, potentially r esulting in decreased levels of surface mannose receptor available for Ag o r pathogen capture.