Journal Article

Retinol Binding Protein 4 reactivates latent HIV-1 by triggering canonical NF-κB, JAK/STAT5 and JNK signalling

Rodríguez, Armando, Fair, Matthew, Sparrer, Konstantin M. J., Tebas, Pablo, Gosálbez, Guillermo, Sauertnik, Alina, Koepke, Lennart, Laird, Gregory M., Ständker, Ludger, Du, Yangzhu, Rosenau, Frank, Gaidt, Moritz M., Kirchhoff, Frank, Wiese, Sebastian, Papasavvas, Emmanouil, Montaner, Luis J., Sun, Honghong, Richard, Khumoekae, Morris, Jessicamarie, Preising, Andrea, Usmani, Shariq, Liu, Qin, Hayn, Manuel, Pastorio, Chiara, Kissmann, Ann-Kathrin, Jaritz, Markus, Preising, Nico, Bolotnikov, Grigory, Mounzer, Karam

2025

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/255 / 692/308/2778 / Acid production / Acquired immune deficiency syndrome / AIDS / Antiretroviral therapy / Cancer Research / Cell Biology / Cell lines / HIV / HIV Infections - genetics / HIV Infections - virology / HIV-1 - genetics / HIV-1 - pathogenicity / Human immunodeficiency virus / Humans / Internal Medicine / Janus Kinases - genetics / Kinases / Latency / Latent infection / Lymphocytes T / MAP Kinase Signaling System - genetics / Medicine / Medicine & Public Health / NF-kappa B - genetics / NF-κB protein / Oncology / Pathology / Retinoic acid / Retinol-Binding Proteins, Plasma - genetics / Retinol-Binding Proteins, Plasma - metabolism / Signal transduction / Stat5 protein / STAT5 Transcription Factor - genetics / Tumor necrosis factor-TNF / Virus Activation - genetics / Virus Latency - genetics / Vitamin A