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Productive HIV-1 infection of primary CD4+ T cells induces mitochondrial membrane permeabilization leading to a caspase-independent cell death.
Journal of Biological Chemistry
Date de publication
We have explored in vitro the mechanism by which human immunodeficiency virus, type 1 (HIV-1) induces cell death of primary CD4+ T cells in conditions of productive infection. Although HIV-1 infection primed phytohemagglutinin-activated CD4+ T cells for death induced by anti-CD95 antibody, T cell death was not prevented by a CD95-Fc decoy receptor, nor by decoy receptors of other members of the TNFR family (TNFR1/R2, TRAILR1/R2/OPG, TRAMP) or by various blocking antibodies, suggesting that triggering of death receptors by their cognate ligands is not involved in HIV-induced CD4 T cell death. HIV-1 induced CD4 T cell shrinkage, cell surface exposure of phosphatidylserine, loss of mitochondrial membrane potential (Deltapsim), and mitochondrial release of cytochrome c and apoptosis-inducing factor. A typical apoptotic phenotype (nuclear chromatin condensation and fragmentation) only occurred in around half of the dying cells. Treatment with benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, a broad spectrum caspase inhibitor, prevented nuclear chromatin condensation and fragmentation in HIV-infected CD4+ T cells and in a cell-free system (in which nuclei were incubated with cytoplasmic extracts from the HIV-infected CD4+ T cells). Nevertheless, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone did not prevent mitochondrial membrane potential loss and cell death, suggesting that caspases are dispensable for HIV-mediated cell death. Our findings suggest a major role of the mitochondria in the process of CD4 T cell death induced by HIV, in which targeting of Bax to the mitochondria may be involved.
Animals, Antigens, CD95/metabolism, Apoptosis/physiology, Apoptosis Inducing Factor, CD4-Positive T-Lymphocytes/drug effects, CD4-Positive T-Lymphocytes/metabolism, Caspases/antagonists &, inhibitors, Caspases/metabolism, Cell Death, Cell-Free System/metabolism, Cells, Cultured, Cysteine Proteinase Inhibitors/metabolism, Cytochrome c Group/metabolism, Enzyme Activation, Flavoproteins/metabolism, Flow Cytometry, HIV-1/physiology, Humans, Inhibitor of Apoptosis Proteins, Interleukin-2/pharmacology, Intracellular Membranes/metabolism, Membrane Proteins/metabolism, Mitochondria/metabolism, Permeability, Phytohemagglutinins/pharmacology, Protein Precursors/metabolism, Proto-Oncogene Proteins/metabolism, Proto-Oncogene Proteins c-bcl-2, Receptors, Tumor Necrosis Factor/metabolism, Viral Proteins/metabolism, bcl-2-Associated X Protein
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