Journal Article

DZNE-2025-01140

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Retinol Binding Protein 4 reactivates latent HIV-1 by triggering canonical NF-κB, JAK/STAT5 and JNK signalling.

Pastorio, C. ; Richard, K. ; Usmani, S. ; Kissmann, A.-K. ; Bolotnikov, G. ; Gosálbez, G. ; Hayn, M. ; Koepke, L. ; Sauertnik, A. ; Preising, A. ; Preising, N. ; Ständker, L. ; Fair, M. ; Morris, J. ; Papasavvas, E. ; Liu, Q. ; Sun, H. ; Rodríguez, A. ; Mounzer, K. ; Wiese, S. ; Tebas, P. ; Du, Y. ; Laird, G. M. ; Jaritz, M. ; Rosenau, F. ; Gaidt, M. M. ; Sparrer, K. M. J.DZNE* ; Montaner, L. J. ; Kirchhoff, F.

2025
Macmillan Publishers, part of Springer Nature London

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Please use a persistent id in citations: 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.

Keyword(s): Humans (MeSH) ; HIV-1: genetics (MeSH) ; HIV-1: pathogenicity (MeSH) ; NF-kappa B: genetics (MeSH) ; Virus Latency: genetics (MeSH) ; HIV Infections: genetics (MeSH) ; HIV Infections: virology (MeSH) ; Retinol-Binding Proteins, Plasma: genetics (MeSH) ; Retinol-Binding Proteins, Plasma: metabolism (MeSH) ; Virus Activation: genetics (MeSH) ; STAT5 Transcription Factor: genetics (MeSH) ; Janus Kinases: genetics (MeSH) ; MAP Kinase Signaling System: genetics (MeSH) ; NF-kappa B ; Retinol-Binding Proteins, Plasma ; RBP4 protein, human ; STAT5 Transcription Factor ; Janus Kinases

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Contributing Institute(s):

1. Neurovirology and Neuroinflammation (AG Sparrer)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

Appears in the scientific report 2025

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Database coverage:
; ; ; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 30 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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