Apoptotic killing of HIV-1-infected macrophages is subverted by the viral envelope glycoprotein.
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.
Swingler
Simon
S
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Mann
Angela M
AM
Zhou
Jin
J
Swingler
Catherine
C
Stevenson
Mario
M
D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D015686:Gene Products, env / Q000502:physiology*; D015658:HIV Infections / Q000473:pathology*; D015497:HIV-1; D006801:Humans; D000068877:Imatinib Mesylate; D016173:Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D008264:Macrophages / Q000821:virology*; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis*
D001549:Benzamides; D015686:Gene Products, env; D010879:Piperazines; D011743:Pyrimidines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D016173:Macrophage Colony-Stimulating Factor; D000068877:Imatinib Mesylate