Mitochondrion-dependent caspase activation by the HIV-1 envelope.
Cells expressing the envelope glycoprotein complex (Env) encoded by the human immunodeficiency virus can fuse with cells expressing Env receptors (CD4 and CXCR4). The resulting syncytia undergo apoptosis. We developed a cytofluorometric assay for the quantitation of syncytium formation and syncytial apoptosis. Using this methodology, we show that caspase activation in syncytia is inhibited by pharmacological or genetic intervention on cyclin-dependent kinase-1, p53, and mitochondrial membrane permeabilization (MMP). Thus, transfection of fusing cells with the viral mitochondrial inhibitor of apoptosis encoded by cytomegalovirus, a specific inhibitor of MMP, prevented the mitochondrial cytochrome c release and abolished simultaneously the activation of caspase-3. Conversely, inhibition of caspases did not prevent MMP. These results indicate that Env-elicited syncytial apoptosis involves the intrinsic (mitochondrial) pathway.
Roumier
Thomas
T
Centre National de la Recherche Scientifique, UMR 8125, Institut Gustave Roussy, 39 rue Camille-Desmoulins, F-94805 Villejuif, France.
Castedo
Maria
M
Perfettini
Jean-Luc
JL
Andreau
Karine
K
Métivier
Didier
D
Zamzami
Naoufal
N
Kroemer
Guido
G
D017209:Apoptosis; D016203:CDC2 Protein Kinase / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D015726:Giant Cells / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D014759:Viral Envelope Proteins / Q000494:pharmacology*
D014759:Viral Envelope Proteins; D045304:Cytochromes c; D016203:CDC2 Protein Kinase; D020169:Caspases