REGULATION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 GENE-TRANSCRIPTION BY NUCLEAR RECEPTORS IN HUMAN BRAIN-CELLS

Infection of cells of the central nervous system by the human immunode ficiency virus type-1 (HIV-1) leads to HIV-1-associated neuropathology . Recent studies have demonstrated the importance of long terminal rep eat (LTR) binding sites in determining the pathogenicity of HIV. Here we have investigated the presence and the functional role of transcrip tion factors that have the potential to interact, directly or indirect ly, with the nuclear receptor-responsive element in the LTR of HIV-1, in different human cell lines of the brain. Cotransfection experiments showed that in oligodendroglioma TC-620 cells, the retinoic acid rece ptor and the retinoid X receptor activate LTR-driven transcription in the absence of ligand. Addition of all trans- or 9-cis-retinoic acid r everses this effect. In contrast, in astrocytoma, neuronal, and microg lial cells, no significant effect of the retinoid acid pathway was det ected. This retinoid response is mediated by distinct molecular intera ctions in the lymphotropic LAI and the neurotropic JR-CSF HIV-1 strain s. Moreover, retinoid receptors were found to antagonize the chicken o valbumin upstream promoter transcription factor- as well as the c-JUN- mediated LTR transactivation, Our findings demonstrate the importance of the retinoic acid signaling pathway and of cross coupling interacti ons in the repression of HIV-1 LTR gene expression.