title: A dynamic G-quadruplex region regulates the HIV-1 long terminal repeat promoter.
abstract: G-Quadruplexes, noncanonical nucleic acid structures, act as silencers in the promoter regions of human genes; putative G-quadruplex forming sequences are also present in promoters of other mammals, yeasts, and prokaryotes. Here we show that also the HIV-1 LTR promoter exploits G-quadruplex-mediated transcriptional regulation with striking similarities to eukaryotic promoters and that treatment with a G-quadruplex ligand inhibits HIV-1 infectivity. Computational analysis on 953 HIV-1 strains substantiated a highly conserved G-rich sequence corresponding to Sp1 and NF-κB binding sites. Biophysical/biochemical analysis proved that two mutually exclusive parallel-like intramolecular G-quadruplexes, stabilized by small molecule ligands, primarily fold in this region. Mutations disrupting G-quadruplex formation enhanced HIV promoter activity in cells, whereas treatment with a G-quadruplex ligand impaired promoter activity and displayed antiviral effects. These findings disclose the possibility of inhibiting the HIV-1 LTR promoter by G-quadruplex-interacting small molecules, providing a new pathway to development of anti-HIV-1 drugs with unprecedented mechanism of action.
authors.affiliation: Department of Molecular Medicine, University of Padua, Italy.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Perrone
authors.forename: Matteo
authors.initials: M
authors.lastname: Nadai
authors.forename: Ilaria
authors.initials: I
authors.lastname: Frasson
authors.forename: Jerrod A
authors.initials: JA
authors.lastname: Poe
authors.forename: Elena
authors.initials: E
authors.lastname: Butovskaya
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Smithgall
authors.forename: Manlio
authors.initials: M
authors.lastname: Palumbo
authors.forename: Giorgio
authors.initials: G
authors.lastname: Palù
authors.forename: Sara N
authors.initials: SN
authors.lastname: Richter
mesh_terms: D054856:G-Quadruplexes; D057809:HEK293 Cells; D016325:HIV Long Terminal Repeat / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D011401:Promoter Regions, Genetic