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bioRxiv · 10.64898/2025.12.10.693434

Synchronized Latency Reversal and Immune Clearance by a Multifunctional Fusion Protein Enables HIV-1 Reservoir Reduction

Luo, F.·Cao, Y.·Liu, N.·Wang, X.·Hu, W.·Xie, X.·Jiang, D.·Xu, Y.·Wang, J.·Wang, H.·Yu, Z.·Qian, P.·Wan, S.·Liu, Z.·Chen, T.·Song, S.·Xiong, Y.·Tang, X.·Li, L.·Wang, L.·Yu, H.·Cheng, L.
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Abstract

Strategies that concurrently reactivate latent reservoirs and enhance immune-mediated clearance hold significant promise for achieving an HIV cure. Here, we developed hyperIL-15xsCD4-Fc (15xsCD4-Fc), a fusion protein that integrates latency reactivation, targeted immune engagement, and effector-mediated killing into a single molecule. This agent not only potently reverses HIV-1 latency in CD4+ T cells from people living with HIV-1 (PLWH) through coordinated IL-15 receptor signaling and sCD4-mediated HIV-1 envelope (Env) engagement, but also enhances antigen-specific CD8+ T cell response in PBMCs derived from PLWH. Furthermore, 15xsCD4-Fc enables Env-specific elimination of reactivated latently infected cells by NK cells while preventing off-target cytotoxicity. In PBMCs from PLWH, 15xsCD4-Fc reduced replication-competent HIV-1 DNA by 93.8%. In antiretroviral treated HIV-1-infected humanized mice, the molecule demonstrated both safety and efficacy in diminishing viral reservoir in lymphoid organs. This spatiotemporally coupled approach to reservoir exposure and immune recognition establishes a clinically viable strategy for clearing the HIV-1 reservoir. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/693434v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@8f8f0org.highwire.dtl.DTLVardef@10f63f7org.highwire.dtl.DTLVardef@16c1de2org.highwire.dtl.DTLVardef@11e1787_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Luo, F., Cao, Y., Liu, N., Wang, X., Hu, W., Xie, X., Jiang, D., Xu, Y., Wang, J., Wang, H., Yu, Z., Qian, P., Wan, S., Liu, Z., Chen, T., Song, S., Xiong, Y., Tang, X., Li, L., Wang, L., Yu, H., Cheng, L.. 2025-12-13. Synchronized Latency Reversal and Immune Clearance by a Multifunctional Fusion Protein Enables HIV-1 Reservoir Reduction. https://doi.org/10.64898/2025.12.10.693434

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