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Apoptotic Killing of HIV-1–Infected Macrophages Is Subverted by the Viral Envelope Glycoprotein * Simon Swingler, Angela M. Mann, Jin Zhou, Catherine Swingler, Mario Stevenson Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America 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 factor–related apoptosis-inducing ligand). In HIV-1–infected 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-1–infected macrophages, suggesting a novel strategy to curtail viral persistence in the macrophage reservoir. Citation: Swingler S, Mann AM, Zhou J, Swingler C, Stevenson M (2007) Apoptotic killing of HIV-1–infected macrophages is subverted by the viral envelope glycoprotein. PLoS Pathog 3(9): e134. doi:10.1371/journal.ppat.0030134 Introduction apoptotic response, productively infected lymphocytes are rapidly cleared by the cytopathic effects of virus infection The envelope glycoproteins of primate lentiviruses harbor [15]. By comparison, the turnover of infected macrophages is domains