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Original Article

^a Centre National de la Recherche Scientifique, UMR1599, Institut Gustave Roussy, F-94805 Villejuif, France
^b Institut de Recerca de la SIDA-Caixa, Laboratori de Retrovirologia, Hospital Universitari Germans Trias i Pujol, Universitat Autónoma de Barcelona, 08916 Badalona, Catalonia, Spain
^c Istituto Nazionale Malattie Infettive "L. Spallanzani", University of Rome Tor Vergata, Rome 00133, Italy
^d Department of Biology, University of Rome Tor Vergata, Rome 00133, Italy
CNRS-UMR1599, Institut Gustave Roussy, Pavillon de Recherche 1, 39 rue Camille-Desmoulins, F-94805 Villejuif, France.33-1-4211-604733-1-4211-6046

kroemer{at}igr.fr

Syncytia arising from the fusion of cells expressing a lymphotropic human immunodeficiency virus (HIV)-1–encoded envelope glycoprotein complex (Env) gene with cells expressing the CD4/CXCR4 complex undergo apoptosis through a mitochondrion-controlled pathway initiated by the upregulation of Bax. In syncytial apoptosis, phosphorylation of p53 on serine 15 (p53S15) precedes Bax upregulation, the apoptosis-linked conformational change of Bax, the insertion of Bax in mitochondrial membranes, subsequent release of cytochrome c, caspase activation, and apoptosis. p53S15 phosphorylation also occurs in vivo, in HIV-1⁺ donors, where it can be detected in preapoptotic and apoptotic syncytia in lymph nodes, as well as in peripheral blood mononuclear cells, correlating with viral load. Syncytium-induced p53S15 phosphorylation is mediated by the upregulation/activation of mammalian target of rapamycin (mTOR), also called FKBP12-rapamycin-associated protein (FRAP), which coimmunoprecipitates with p53. Inhibition of mTOR/FRAP by rapamycin reduces apoptosis in several paradigms of syncytium-dependent death, including in primary CD4⁺ lymphoblasts infected by HIV-1. Concomitantly, rapamycin inhibits p53S15 phosphorylation, mitochondrial translocation of Bax, loss of the mitochondrial transmembrane potential, mitochondrial release of cytochrome c, and nuclear chromatin condensation. Transfection with dominant negative p53 has a similar antiapoptotic action as rapamycin, upstream of the Bax upregulation/translocation. In summary, we demonstrate that phosphorylation of p53S15 by mTOR/FRAP plays a critical role in syncytial apoptosis driven by HIV-1 Env.

Key Words: cell death • envelope glycoprotein complex • human immunodeficiency virus • mitochondria • rapamycin

Abbreviations used in this paper: 4EBP, 4E-binding protein; ATM, ataxia teleangiectasia mutated; ATR, ataxia teleangiectasia Rad3; Cyt. c, cytochrome c; DNA-PK, DNA-dependent protein kinase; Env, envelope glycoprotein complex; FRAP, FKBP12-rapamycin-associated protein; GFP, green fluorescent protein; MEF, mouse embryonic fibroblast; MMP, mitochondrial membrane permeabilization; mTOR, mammalian target of rapamycin; PEG, polyethylene glycol; PIKK, phosphatidylinositol kinase-related kinases; SC, single cell; TOP, terminal oligopyrimidine; tTGase, tissue transglutaminase.

© 2001 The Rockefeller University Press

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