TY  - JOUR
AU  - Pastorio, Chiara
AU  - Richard, Khumoekae
AU  - Usmani, Shariq
AU  - Kissmann, Ann-Kathrin
AU  - Bolotnikov, Grigory
AU  - Gosálbez, Guillermo
AU  - Hayn, Manuel
AU  - Koepke, Lennart
AU  - Sauertnik, Alina
AU  - Preising, Andrea
AU  - Preising, Nico
AU  - Ständker, Ludger
AU  - Fair, Matthew
AU  - Morris, Jessicamarie
AU  - Papasavvas, Emmanouil
AU  - Liu, Qin
AU  - Sun, Honghong
AU  - Rodríguez, Armando
AU  - Mounzer, Karam
AU  - Wiese, Sebastian
AU  - Tebas, Pablo
AU  - Du, Yangzhu
AU  - Laird, Gregory M
AU  - Jaritz, Markus
AU  - Rosenau, Frank
AU  - Gaidt, Moritz M
AU  - Sparrer, Konstantin M J
AU  - Montaner, Luis J
AU  - Kirchhoff, Frank
TI  - Retinol Binding Protein 4 reactivates latent HIV-1 by triggering canonical NF-κB, JAK/STAT5 and JNK signalling.
JO  - Signal transduction and targeted therapy
VL  - 10
IS  - 1
SN  - 2095-9907
CY  - London
PB  - Macmillan Publishers, part of Springer Nature
M1  - DZNE-2025-01140
SP  - 326
PY  - 2025
AB  - 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.
KW  - Humans
KW  - HIV-1: genetics
KW  - HIV-1: pathogenicity
KW  - NF-kappa B: genetics
KW  - Virus Latency: genetics
KW  - HIV Infections: genetics
KW  - HIV Infections: virology
KW  - Retinol-Binding Proteins, Plasma: genetics
KW  - Retinol-Binding Proteins, Plasma: metabolism
KW  - Virus Activation: genetics
KW  - STAT5 Transcription Factor: genetics
KW  - Janus Kinases: genetics
KW  - MAP Kinase Signaling System: genetics
KW  - NF-kappa B (NLM Chemicals)
KW  - Retinol-Binding Proteins, Plasma (NLM Chemicals)
KW  - RBP4 protein, human (NLM Chemicals)
KW  - STAT5 Transcription Factor (NLM Chemicals)
KW  - Janus Kinases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41038866
C2  - pmc:PMC12491451
DO  - DOI:10.1038/s41392-025-02424-3
UR  - https://pub.dzne.de/record/281522
ER  -