title: Productive HIV-1 infection of primary CD4+ T cells induces mitochondrial membrane permeabilization leading to a caspase-independent cell death.
abstract: 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.
authors.affiliation: INSERM EMI-U 9922, CHU Bichat, Université Paris 7, 16 rue Henri Huchard, 75018 Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Petit
authors.forename: Damien
authors.initials: D
authors.lastname: Arnoult
authors.forename: Jean-Daniel
authors.initials: JD
authors.lastname: Lelièvre
authors.forename: Laure
authors.initials: L
authors.lastname: Moutouh-de Parseval
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Hance
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
authors.forename: Jacques
authors.initials: J
authors.lastname: Corbeil
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Ameisen
authors.forename: Jérôme
authors.initials: J
authors.lastname: Estaquier
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051033:Apoptosis Inducing Factor; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology / Q000821:virology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death; D002474:Cell-Free System / Q000378:metabolism; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation; D005420:Flavoproteins / Q000378:metabolism; D005434:Flow Cytometry; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007376:Interleukin-2 / Q000494:pharmacology; D007425:Intracellular Membranes / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D010539:Permeability; D010835:Phytohemagglutinins / Q000494:pharmacology; D011498:Protein Precursors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000378:metabolism
chemical_list: C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; C494826:BAX protein, human; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D003574:Cytochrome c Group; D005420:Flavoproteins; D051034:Inhibitor of Apoptosis Proteins; D007376:Interleukin-2; D008565:Membrane Proteins; D010835:Phytohemagglutinins; D011498:Protein Precursors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D014764:Viral Proteins; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; C086430:inhibitor of apoptosis, Nucleopolyhedrovirus; D020169:Caspases