Retinol Binding Protein 4 reactivates latent HIV-1 by triggering canonical NF-κB, JAK/STAT5 and JNK signalling
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.
Authors
- Ludger Ständker
- Lennart Koepke (ORCID: https://orcid.org/0000-0001-9788-1972)
- Andrea Preising
- Karam Mounzer (ORCID: https://orcid.org/0000-0001-8537-7103)
- Frank Rosenau (ORCID: https://orcid.org/0000-0002-9297-6419)
- Sebastian Wiese (ORCID: https://orcid.org/0000-0001-5697-2608)
- Moritz M. Gaidt (ORCID: https://orcid.org/0000-0002-8009-294X)
- Chiara Pastorio (ORCID: https://orcid.org/0000-0002-4745-3678)
- Yangzhu Du (ORCID: https://orcid.org/0000-0002-1471-8692)
- Shariq M. Usmani (ORCID: https://orcid.org/0000-0002-6462-1098)
- Manuel Hayn (ORCID: https://orcid.org/0000-0001-5908-3099)
- Konstantin M. J. Sparrer (ORCID: https://orcid.org/0000-0002-8682-1779)
- Armando Rodríguez (ORCID: https://orcid.org/0000-0001-5921-3770)
- Emmanouil Papasavvas
- Pablo Tebas (ORCID: https://orcid.org/0000-0001-5345-7942)
- Markus Jaritz (ORCID: https://orcid.org/0000-0002-9326-2047)
- Luis J. Montaner (ORCID: https://orcid.org/0000-0001-5799-6759)
- Frank Kirchhoff (ORCID: https://orcid.org/0000-0002-7052-2360)
- Gregory M. Laird (ORCID: https://orcid.org/0000-0003-2873-4295)
- Nico Preising
- Khumoekae Richard (ORCID: https://orcid.org/0000-0002-7523-0025)
- Matthew Fair
- Ann‐Kathrin Kissmann (ORCID: https://orcid.org/0000-0002-7164-0166)
- Grigory Bolotnikov
- Qin Liu (ORCID: https://orcid.org/0000-0002-8916-5711)
- Jessicamarie Morris
- Honghong Sun
- Guillermo Gosálbez
- Alina Sauertnik
Institutions
- The Wistar Institute (US)
- Research Institute of Molecular Pathology (AT)
- Universität Ulm (DE)
- German Center for Neurodegenerative Diseases (DE)
- University Hospital Ulm (DE)
- University of Pennsylvania (US)
Publication Details
- Journal
- Signal Transduction and Targeted Therapy
- Published
- 2025-10-02
- DOI
- https://doi.org/10.1038/s41392-025-02424-3
- Primary Topic
- Retinoids in leukemia and cellular processes
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- University of Pennsylvania
- Philadelphia Foundation
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- Perelman School of Medicine, University of Pennsylvania