1. SMAC Mimetics Induce Autophagy-Dependent Apoptosis of HIV-1-Infected Resting Memory CD4+ T Cells.
- Author
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Campbell GR, Bruckman RS, Chu YL, Trout RN, and Spector SA
- Subjects
- Apoptosis Regulatory Proteins, Autophagy-Related Protein 5 metabolism, Autophagy-Related Protein 7 metabolism, Baculoviral IAP Repeat-Containing 3 Protein metabolism, Beclin-1 metabolism, Benzoquinones pharmacology, Caspase 8 metabolism, Cell Death, Cell Line, Cyclohexanes pharmacology, Dipeptides pharmacology, Fas-Associated Death Domain Protein metabolism, HIV-1 pathogenicity, Humans, Indoles pharmacology, Inhibitor of Apoptosis Proteins metabolism, Intracellular Signaling Peptides and Proteins metabolism, Mitochondrial Proteins metabolism, Pyrroles pharmacology, Receptor-Interacting Protein Serine-Threonine Kinases metabolism, Sequestosome-1 Protein metabolism, Ubiquitin-Protein Ligases metabolism, X-Linked Inhibitor of Apoptosis Protein metabolism, Apoptosis drug effects, Apoptosis physiology, Autophagy drug effects, Autophagy physiology, CD4-Positive T-Lymphocytes immunology, HIV Infections immunology, HIV-1 drug effects, HIV-1 physiology
- Abstract
Long-lived resting memory CD4+ T cells (T
CM ) are a major reservoir of latent HIV infection. We hypothesized that latent HIV-TCM cells are maintained by aberrant expression of cell survival factors, including XIAP, BIRC2/cIAP1, and beclin-1. DIABLO/SMAC mimetics are therapeutic agents that compromise cell survival by hijacking host apoptotic machinery. We found that DIABLO/SMAC mimetics (birinapant, GDC-0152, and embelin) selectively kill HIV-TCM without increasing virus production or targeting uninfected TCM . Treatment of HIV-TCM with DIABLO/SMAC mimetics promoted XIAP and BIRC2 degradation, which triggered autophagy and the formation of a cell death complex consisting of pro-apoptotic (FADD, RIPK1, RIPK3, and caspase 8) and autophagy (ATG5, ATG7, and SQSTM1) proteins. Genetic or pharmacological inhibition of autophagy induction, but not autophagy-mediated degradation, abrogated this interaction and subsequent cell death. Our findings identify a mechanism whereby DIABLO/SMAC mimetics exploit autophagy and apoptotic machinery to selectively induce killing of HIV-TCM without viral reactivation while sparing uninfected cells., (Copyright © 2018 Elsevier Inc. All rights reserved.)- Published
- 2018
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