Contagious apoptosis facilitated by the HIV-1 envelope: fusion-induced cell-to-cell transmission of a lethal signal.
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+ 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.
Andreau
Karine
K
CNRS-UMR8125, France.
Perfettini
Jean-Luc
JL
Castedo
Maria
M
Métivier
Didier
D
Scott
Véronique
V
Pierron
Gérard
G
Kroemer
Guido
G
D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D024201:Bystander Effect / Q000187:drug effects / Q000502:physiology; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D018920:Coculture Techniques; D004272:DNA, Mitochondrial / Q000502:physiology; D004791:Enzyme Inhibitors / Q000633:toxicity; D015686:Gene Products, env / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020868:Gene Silencing; D017930:Genes, Reporter; D015726:Giant Cells / Q000473:pathology; D015700:HIV Envelope Protein gp41 / Q000494:pharmacology; D015497:HIV-1; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D010446:Peptide Fragments / Q000494:pharmacology / Q000633:toxicity; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology*; D014162:Transfection
D015704:CD4 Antigens; D004272:DNA, Mitochondrial; D004791:Enzyme Inhibitors; D015686:Gene Products, env; D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; C407149:peptide C34; D020169:Caspases