Viruses have evolved strategies to protect infected cells from
apoptotic clearance. We present evidence that HIV-1 possesses
a mechanism to protect infected
macrophages from the apoptotic effects of the death ligand TRAIL (tumor necrosis factorrelated apoptosis-inducing ligand). In HIV-1infected macrophages, the viral envelope protein induced macrophage colony-stimulating factor (M-CSF). This pro-survival cytokine downregulated the TRAIL
receptor TRAIL-R1/DR4 and upregulated the anti-apoptotic genes Bfl-1 and Mcl-1. Inhibition of M-CSF activity or silencing of Bfl-1 and Mcl-1 rendered infected macrophages highly susceptible to TRAIL. The anti-cancer agent Imatinib inhibited M-CSF receptor activation and restored the apoptotic sensitivity of HIV-1infected macrophages, suggesting a novel strategy to curtail viral persistence in the macrophage reservoir.