Bivalent SMAC mimetic APG-1387 reduces HIV reservoirs and limits viral rebound in humanized mice

Latent viral reservoirs (VRs) represent a main barrier to HIV cure. Thus, developing new approaches that can purge and eliminate VRs paves the path toward achieving an HIV-1 cure. APG-1387, a bivalent SMAC mimetic (SM), efficiently reactivates latent HIV expression in T cell line models and enhances active caspase 3 expression, a condition that typically leads to apoptosis. In primary CD4+ T cells infected with a dual reporter-encoded HIV, APG-1387 decreases latently infected cells without a notable effect on productively infected cells. In virally suppressed humanized (hu)-BLT mice, APG-1387 augments cell-associated viral RNA and potently reduces HIV DNA-containing cells without modulating T cell activation or proliferation. Upon antiretroviral therapy (ART) interruption, HIV rebound was decreased in APG-1387-treated humanized mice (hu-mice), and the viremia maintained at levels below that of pre-ART. Thus, the ability of APG-1387 to affect VRs and decrease viral rebound highlights the potential of bivalent SMs in HIV cure strategies. [Display omitted] •APG-1387 reactivates HIV expression and enhances caspase 3 levels in latent cells•The compound does not affect global T cell proliferation or activation in hu-BLT mice•APG-1387 reduces latently infected cells in tissues of ART-suppressed hu-BLT mice•Viral rebound upon treatment interruption is lowered in APG-1387-treated hu-mice Immunology; Virology; Natural sciences; Biological sciences