%0 Journal Article
%A Pastorio, Chiara
%A Richard, Khumoekae
%A Usmani, Shariq
%A Kissmann, Ann-Kathrin
%A Bolotnikov, Grigory
%A Gosálbez, Guillermo
%A Hayn, Manuel
%A Koepke, Lennart
%A Sauertnik, Alina
%A Preising, Andrea
%A Preising, Nico
%A Ständker, Ludger
%A Fair, Matthew
%A Morris, Jessicamarie
%A Papasavvas, Emmanouil
%A Liu, Qin
%A Sun, Honghong
%A Rodríguez, Armando
%A Mounzer, Karam
%A Wiese, Sebastian
%A Tebas, Pablo
%A Du, Yangzhu
%A Laird, Gregory M
%A Jaritz, Markus
%A Rosenau, Frank
%A Gaidt, Moritz M
%A Sparrer, Konstantin M J
%A Montaner, Luis J
%A Kirchhoff, Frank
%T Retinol Binding Protein 4 reactivates latent HIV-1 by triggering canonical NF-κB, JAK/STAT5 and JNK signalling.
%J Signal transduction and targeted therapy
%V 10
%N 1
%@ 2095-9907
%C London
%I Macmillan Publishers, part of Springer Nature
%M DZNE-2025-01140
%P 326
%D 2025
%X Reactivation of the latent viral reservoirs is crucial for a cure of HIV/AIDS. However, current latency reversing agents are inefficient, and the endogenous factors that have the potential to reactivate HIV in vivo remain poorly understood. To identify natural activators of latent HIV-1, we screened a comprehensive peptide/protein library derived from human hemofiltrate, representing the entire blood peptidome, using J-Lat cell lines harboring transcriptionally silent HIV-1 GFP reporter viruses. Fractions potently reactivating HIV-1 from latency contained human Retinol Binding Protein 4 (RBP4), the carrier of retinol (Vitamin A). We found that retinol-bound holo-RBP4 but not retinol-free apo-RBP4 strongly reactivates HIV-1 in a variety of latently infected T cell lines. Functional analyses indicate that this reactivation involves activation of the canonical NF-κB pathway and is strengthened by JAK/STAT5 and JNK signalling but does not require retinoic acid production. High levels of RBP4 were detected in plasma from both healthy individuals and people living with HIV-1. Physiological concentrations of RBP4 induced significant viral reactivation in latently infected cells from individuals on long-term antiretroviral therapy with undetectable viral loads. As a potent natural HIV-1 latency-reversing agent, RBP4 offers a novel approach to activating the latent reservoirs and bringing us closer to a cure.
%K Humans
%K HIV-1: genetics
%K HIV-1: pathogenicity
%K NF-kappa B: genetics
%K Virus Latency: genetics
%K HIV Infections: genetics
%K HIV Infections: virology
%K Retinol-Binding Proteins, Plasma: genetics
%K Retinol-Binding Proteins, Plasma: metabolism
%K Virus Activation: genetics
%K STAT5 Transcription Factor: genetics
%K Janus Kinases: genetics
%K MAP Kinase Signaling System: genetics
%K NF-kappa B (NLM Chemicals)
%K Retinol-Binding Proteins, Plasma (NLM Chemicals)
%K RBP4 protein, human (NLM Chemicals)
%K STAT5 Transcription Factor (NLM Chemicals)
%K Janus Kinases (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:41038866
%2 pmc:PMC12491451
%R 10.1038/s41392-025-02424-3
%U https://pub.dzne.de/record/281522