Dickkopf-1: Endogenous HIV Latency Modulation

• Applicant: Dr. Jasmin Jäger
• Subject Area: Clinical Infectiology and Tropical Medicine
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 574128666

Despite effective antiretroviral therapy (ART), HIV infection remains incurable due to the persistence of a latent viral reservoir. This reservoir, primarily composed of resting CD4⁺ T cells harboring transcriptionally silent but replication-competent HIV proviruses, represents the major barrier to viral eradication. Strategies such as "shock and kill" aim to pharmacologically reactivate the latent reservoir, rendering infected cells visible to immune clearance mechanisms. Central to this approach are latency-reversing agents (LRA) that disrupt transcriptional silencing and trigger viral gene expression. One recently identified regulator of HIV latency is the canonical Wnt/β-Catenin signaling pathway, which suppresses HIV transcription through β-catenin-mediated activation of TCF/LEF transcription factors. This project focuses on Dickkopf-1 (DKK1), an endogenous Wnt antagonist that blocks Wnt/β-Catenin signaling by binding to the co-receptors LRP5/6, preventing β-catenin stabilization. Preliminary data from latently infected T cell lines suggest that DKK1 may promote HIV reactivation, particularly in combination with other sub-threshold latency reversing stimuli. The overarching goal of this project is to investigate DKK1 as a novel physiological modulator of HIV latency. Unlike synthetic LRAs, DKK1 is a naturally secreted protein that may provide a safer, more targeted approach to modulate viral transcription. The project comprises three interconnected aims: 1. Characterize the Wnt signaling axis in latently infected T cell models and primary CD4⁺ T cells from ART-treated PLWH, including baseline expression of Wnt ligands, receptors, and downstream components. 2. Establish whether the Wnt/β-catenin signaling cascade can be modulated to reverse latency, using known pharmacological activators to induce HIV transcription and benchmark DKK1’s effect. 3. Assess the latency-reversing capacity of recombinant DKK1, both as a standalone agent and in combination with other LRAs, in latently infected T cell lines and ex vivo primary CD4⁺ T cells. All experimental work will be conducted at the Institute for HIV and AIDS-Associated Diseases (HIV-AAD) at the University of Duisburg-Essen, using established latency models and validated analytical techniques including flow cytometry, qRT-PCR, and ddPCR. Patient recruitment and primary cell isolation will be coordinated through the HIV outpatient clinic at University Hospital Essen, ensuring access to clinically relevant samples. By elucidating the regulatory role of DKK1 in the Wnt/β-Catenin axis and its impact on HIV latency, this project aims to uncover a novel biological mechanism for reservoir reactivation. Ultimately, the findings may inform the development of less toxic, host-directed interventions that enhance the efficacy and safety of future HIV cure strategies.

• DFG Programme: Research Grants