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
  • 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. [email protected].
  • # 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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