Abstract
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.
Highlights
The core tor-responsive element(NRRE), spans the -356 to -320 promoter element (-1 to -78) which is critical for both basal
The NRRE interacts with heterodimers formed betweenRXRa and either ARF"1, EAR-2, EAR-3, the retinoic acid receptor-a (RARa),or the peroxisome
In the present study, we have identified a large number of nuclear receptor binding is conserved in the LTRs of nuclear hormone receptors that have the potential to interact recently evolved HIV-1 strains but it is absent in the with sequences withinthe modulatory regionof the HIV-1LTR, oldest and most divergent viralisolates, raising the in- suggesting that a complex network of physiologic signals may triguing possibility that thMe JRE has been evolvedre- converge onto this element and modulate HIV-1 gene exprescently in the viral genome
Summary
0 1994 by The American Society for Biochemistry and Molecular Biology, Inc. Vol 269, No 8,Issue of February 25, pp. 5944-5951, 1994 Printed in U.S.A. The abbreviations used are: HrV-1, human immunodeficiency virus-I; NRRE, nuclear receptor-responsiveelement; RXRa, retinoid X receptor-a; ARP-1, apolipoprotein AI regulatory protein-1; EAR-2,verbA-related protein-2; EAR-3, v-erbA-related protein-3; HNF-4, hepatocyte nuclear factor-4; NGFI-B, nerve growth factor-inducible protein-B; RARo,retinoic acid receptor-a; PPAR, peroxisome proliferatoractivated receptor; EMSA, electrophoretic mobility shift assay; PCR, PCR using the primers 5'-GATCCGCTCGAGCTGGAAGGGCTAATTCACTCCCAACGAAGA-3' and 5'-GCACTCAAGGCAAGCT"ATTGAGGCTTAAGCAGTGGGTTCCCTA-3' and plasmid pUC-BENN-CAT (AIDS Research and Reference Reagent Program, NIH) as a template, followed by digestion with XhoI and Hind111 and ligation with a HindIII-BamHI fragment containing the chloramphenicol acetyltransferase (CAT)gene from pCAT-Promoter vector(Promega),into the XhoIBamHI linearized pGEM-7Zf(+).All constructs wereconfirmedby polymerase chain reaction; CAT, chloramphenicol acetyltransferase; sequencingwith the Sequenase system
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