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

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

  • Signal Transduct Target Ther. 2025 Oct 3;10(1):326. doi: 10.1038/s41392-025-02424-3.
Chiara Pastorio # 1,  Khumoekae Richard # 2,  Shariq Usmani # 1,  Ann-Kathrin Kissmann # 3,  Grigory Bolotnikov 3,  Guillermo Gosálbez 1,  Manuel Hayn 1,  Lennart Koepke 1,  Alina Sauertnik 1,  Andrea Preising 1,  Nico Preising 4,  Ludger Ständker 4,  Matthew Fair 2,  Jessicamarie Morris 2,  Emmanouil Papasavvas 2,  Qin Liu 2,  Honghong Sun 5,  Armando Rodríguez 4 6,  Karam Mounzer 2,  Sebastian Wiese 6,  Pablo Tebas 5,  Yangzhu Du 5,  Gregory M Laird 7,  Markus Jaritz 8,  Frank Rosenau 3,  Moritz M Gaidt 8,  Konstantin M J Sparrer 1 9,  Luis J Montaner 2,  Frank Kirchhoff 10
Affiliations

Affiliations

  • 1 Institute of Molecular Virology, Ulm University Medical Centre, Ulm, Germany.
  • 2 HIV Cure and Viral Diseases Center, The Wistar Institute, Philadelphia, PA, USA.
  • 3 Institute of Pharmaceutical Biotechnology, Ulm University, Ulm, Germany.
  • 4 Core Facility Functional Peptidomics (CFP), Ulm University Medical Center, Ulm, Germany.
  • 5 Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA, USA.
  • 6 Core Unit Mass Spectrometry and Proteomics (CUMP), Ulm University Medical Center, Ulm, Germany.
  • 7 AccelevirDx, Baltimore, MD, USA.
  • 8 Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria.
  • 9 German Center for Neurodegenerative Diseases (DZNE), Ulm, Germany.
  • 10 Institute of Molecular Virology, Ulm University Medical Centre, Ulm, Germany. frank.kirchhoff@uni-ulm.de.
  • # Contributed equally.
PMID: 41038866 DOI: 10.1038/s41392-025-02424-3
Abstract

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.

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