Combined antiretroviral therapy prevents HIV-1 replication and development of AIDS but does not eliminate the virus. This is due to HIV-1 persistence in a small pool of long-living resting CD4⁺ T cells, harboring intact silent proviruses. These cells can reactivate and initiate spreading HIV infection if therapy is stopped, preventing a cure. One strategy to eliminate this reservoir is the "kick-and-kill" approach, which uses latency-reversing agents (LRAs) to reactivate silent proviruses, making infected cells susceptible to immune clearance and antiretroviral drugs. However, current LRAs have shown limited effectiveness in reducing reservoir size and further safe and effective agents are urgently needed.

In an interdisciplinary study, just published in Signal Transduction and Targeted Therapy, members of CRC 1279 together with partners from the US and Austria show that Retinol Binding Protein 4 (RBP4)—the main carrier of vitamin A in the blood—can reactivate latent HIV-1 in human T cells. Screening of a hemofiltrate-derived peptide/protein library revealed that RBP4 triggers HIV-1 activation in T cell lines and the group of Luis Montaner (Wistar Institute, Philadelphia, USA) confirmed significant viral reactivation in latently infected cells from individuals on long-term antiretroviral therapy. Comprehensive functional studies led by Chiara Pastorio (Mol. Virol., Ulm), with significant support from Ann-Kathrin Kissmann and Frank Rosenau (Pharmaceutical Biotechnology, Ulm) revealed that holo-RBP4 (retinol-bound) is required for reactivation and that it involves NF-κB, JAK/STAT5, and JNK signaling, but occurs independently of retinoic acid. Chiara recently received the Jutta and Wilfried Trumpp Foundation Prize from the International Graduate School in Molecular Medicine Ulm (IGradU) for her work on this study and SARS-CoV-2.

These unexpected discoveries identify holo-RBP4 as an effectivenatural latency-reversing agent, and may offer new ways to target and eliminate the hidden HIV reservoirs.

 

Pastorio, C., Richard, K., Usmani, S. et al. Retinol Binding Protein 4 reactivates latent HIV-1 by triggering canonical NF-κB, JAK/STAT5 and JNK signalling. Sig Transduct Target Ther 10, 326 (2025).