Targeting the Rev recognition RNA element of HIV-1

HIV-1 remains one of the leading contributors to the global burden of disease. The complex between several monomers of the HIV-1 Rev protein and the Rev Recognition Element (RRE) in the viral RNA allows nuclear export of unspliced or singly spliced transcripts, an essential step in the virus cycle that is not targeted by any of the currently marketed antiretroviral treatments. The 234-nucleotide RNA component of this complex adopts a multi-domain structure whose three-dimensional details are currently unknown at atomic resolution. To shed light on RRE structure and on the mechanism of RRE-Rev complex assembly, we have set up a method based on fluorescence resonance energy transfer (FRET) that yields information on RRE interdomain distance. By combining this information with all-atom ensemble modelling and electrophoretic assays assessing Rev association, we have generated an atomic model of RRE structure consistent with the available evidence¹. We have also applied the FRET assay to discover small-molecule compounds capable of altering the spatial organization of RRE domains and disrupting the RRE-Rev interaction in vitro and in cellulo². Some of these compounds exhibited antiretroviral activity with favourable selectivity indexes and may serve as valuable leads for the development of novel HIV therapeutics based on specific RRE-Rev inhibition.

(1) Szewczyk, M. P.; Loharch, S.; López-Núñez, S.; Gallego, J. Insights about the structure of the Rev Response Element of HIV-1 revealed by FRET-monitored mutagenesis and modelling. J Mol Biol 2025, 437 (24), 169451. DOI: 10.1016/j.jmb.2025.169451.

(2) Szewczyk, M. P.; Loharch, S.; Izquierdo-Pujol, J.; Beltrán, M.; Puertas, M. C.; Morón-López, S.; Chumillas, S.; Marchán, V.; Alcamí, J.; Martínez-Picado, J.; Bedoya, L. M.; Gallego J. Conformational inhibitors of the HIV-1 Rev Response Element identified through a FRET-based screening approach. Submitted 2025.