mGem: Opening Env and harnessing NK cell effector functions to eliminate HIV-1-infected cells.

Despite effective suppression of viremia by antiretroviral therapy, HIV-1 persists in long-lived cellular reservoirs. Novel approaches aimed at eliminating these reservoirs are therefore essential for an HIV-1 cure. Among emerging cure strategies, harnessing antibody-dependent cellular cytotoxicity (ADCC) has generated significant interest. In this mGem, we discuss how small CD4-mimetic compounds (CD4mc), by forcing envelope (Env) into more "open" conformations, thereby exposing conserved CD4-induced epitopes, can unlock the ADCC potential of non-neutralizing antibodies. We also highlight how type I interferons complement this approach by upregulating BST-2, thereby increasing Env at the cell surface, diminishing Vpu-mediated immune evasion, and enhancing NK cell effector functions. Together, these synergistic interventions provide a promising framework to improve immune recognition of infected cells and potentially reduce the size of the HIV-1 reservoir.