Convergence of multiple nuclear receptor signaling pathways onto the long terminal repeat of human immunodeficiency virus-1.

A composite element that interacts with multiple nuclear receptors has been identified in the long terminal repeat (LTR) of the human immunodeficiency virus-1 (HIV-1). This element, designated nuclear receptor-responsive element (NRRE), spans the -356 to -320 LTR region and contains tightly clustered binding sites for the retinoid X receptor-alpha (RXR alpha) and for five nuclear receptors with unknown ligands, apolipoprotein AI regulatory protein-1 (ARP-1), v-erbA-related proteins-2 and -3 (EAR-2 and EAR-3), hepatocyte nuclear factor-4 (HNF-4), and nerve growth factor-inducible protein-B (NGFI-B). The NRRE also interacts with heterodimers formed between RXR alpha and either ARP-1, EAR-2, EAR-3, the retinoic acid receptor-alpha (RAR alpha), or the peroxisome proliferator-activated receptor (PPAR). Remarkably, nuclear receptor binding is conserved in the LTRs of recently evolved HIV-1 strains but it is absent in the oldest and most divergent viral isolates, raising the intriguing possibility that the NRRE has been evolved recently in the viral genome. Cotransfection experiments in human choriocarcinoma JEG-3 cells have shown that the HIV-1 LTR-driven transcription is activated by RXR alpha and RAR alpha in the presence of 9-cis- and all-trans-retinoic acid, by PPAR and RXR alpha in the presence of clofibric acid and 9-cis-retinoic acid, and by the "orphan" receptors HNF-4 and NGFI-B. These findings suggest that a complex network of nuclear receptor signaling pathways, that include 9-cis- and all-trans-retinoic acid, fatty acids, peroxisome proliferators, growth factors, membrane depolarization, and possibly other signals, converge onto the HIV-1 NRRE and may participate in modulation of viral gene expression.