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HIV induces lymphocyte apoptosis by a p53‐initiated, mitochondrial‐mediated mechanism
Author(s) -
Genini Davide,
Sheeter Dennis,
Rought Steffney,
Zaunders John J.,
Susin Santos A.,
Kroemer Guido,
Richman Douglas D.,
Carson Dennis A.,
Corbeil Jacques,
Leoni Lorenzo M.
Publication year - 2001
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.00-0336fje
Subject(s) - cytochrome c , apoptosis , fadd , mitochondrion , caspase , microbiology and biotechnology , biology , fas ligand , apoptosis inducing factor , phosphorylation , caspase 9 , caspase 8 , programmed cell death , chemistry , biochemistry
HIV‐1 induces apoptosis and leads to CD4+ T‐lymphocyte depletion in humans. It is still unclear whether HIV‐1 kills infected cells directly or indirectly. To elucidate the mechanisms of HIV‐1–induced apoptosis, we infected human CD4+ T cells with HIV‐1. Enzymatic analysis with fluorometric substrates showed that caspase 2, 3, and 9 were activated in CD4+ T cells with peak levels 48 h after infection. Immunoblotting analysis confirmed the cleavage of pro‐caspase 3 and 9, and of specific caspase substrates. Release of cytochrome c and apoptosis‐inducing factor (AIF) from mitochondria was observed in HIV‐infected cells. The cytochrome c and AIF release preceded the reduction of the mitochondrial transmembrane potential and nuclear chromatin condensation. HIV infection led to phosphorylation of p53 at the Ser15 residue, detectable as early as 24 h after infection. The p53 phosphorylation was followed by increased mRNA and protein expression of p21, Bax, HDM2, and p53. Up‐regulation of surface FasL expression, accompanied by a down‐regulation of Fas‐associated proteins (FADD, DAXX, and RIP), was observed 72 h after infection. Our results suggest that HIV activates the p53 pathway, leading to cytochrome c and AIF release with ensuing caspase activation.