Synchronized latency reversal and immune clearance by a multifunctional fusion protein enables HIV-1 reservoir reduction.

Strategies that concurrently reactivate latent reservoirs and enhance immune-mediated clearance hold significant promise for achieving an HIV cure. Here, we developed hyperIL-15×sCD4-Fc (15×sCD4-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 (PLWHs) through coordinated IL-15 receptor signaling and sCD4-mediated HIV-1 envelope (Env) engagement but also enhances the antigen-specific CD8+ T cell response in peripheral blood mononuclear cells (PBMCs) derived from PLWHs. Furthermore, 15×sCD4-Fc enables Env-specific elimination of reactivated latently infected cells by NK cells while preventing off-target cytotoxicity. In PBMCs from PLWHs, 15×sCD4-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 the 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.