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First published online 19 October 2004
doi: 10.1242/jcs.01486

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Contagious apoptosis facilitated by the HIV-1 envelope: fusion-induced cell-to-cell transmission of a lethal signal

¹ CNRS-UMR8125
² Immunology Unit, Department of Clinical Biology, Institut Gustave Roussy, 39 rue Camille-Desmoulins, 94805 Villejuif, France
³ Institut André Lwoff, UPR-1983, Laboratoire Replication de l'ADN et Ultrastructure du Noyau, 7 rue Guy Moquet, 94801 Villejuif, France

^* Author for correspondence (e-mail: kroemer{at}igr.fr)

Accepted 6 August 2004

Cells expressing the human immunodeficiency virus (HIV-1) envelope glycoprotein complex (Env) can fuse with CD4⁺ cells. When the apoptotic pathway is initiated in Env⁺ cells (`donor cells'), co-culture with a healthy CD4<sup>+</sup> fusion partner (`acceptor cells') results in apoptosis of the syncytium and thus is `contagious'. The cell-to-cell transmission of the lethal signal was only observed when the nuclei from donor cells exhibited pre-apoptotic chromatin condensation (PACC), correlating with comet assay-detectable DNA strand breaks, which precede caspase activation, as well as the loss of the mitochondrial transmembrane potential. Transmission of the lethal signal resulted into mitochondrial alterations, and caspase-dependent nuclear pyknosis with chromatinolysis affecting both the donor and the acceptor nuclei. In the presence of caspase inhibitors, all nuclei of the syncytium formed by fusion of the pre-apoptotic and the healthy cell manifested PACC, exhibited DNA lesions and lost transcriptional activity. Transmission of the lethal signal did not require donor cells to contain a nucleus or mitochondrial DNA, yet was inhibited when two mitochondrion-stabilizing proteins, Bcl-2 or vMIA, were overexpressed. Contagious apoptosis could be induced in primary human T cells, as well as in vivo, in T cells exposed to dying Env-expressing cells. Altogether, these data point to a novel mechanism through which HIV-1 can induce bystander killing.

Key words: Mitochondria, Bcl-2, HIV-1, DNA double strand breaks

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