HIV induces lymphocyte apoptosis by a p53-initiated, mitochondrial-mediated mechanism.
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. H IV 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.
Genini
D
D
Department of Medicine, University of California San Diego, La Jolla, California 92093-0663, USA.
Sheeter
D
D
Rought
S
S
Zaunders
J J
JJ
Susin
S A
SA
Kroemer
G
G
Richman
D D
DD
Carson
D A
DA
Corbeil
J
J
Leoni
L M
LM
D017209:Apoptosis; D051033:Apoptosis Inducing Factor; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation; D053222:Fas Ligand Protein; D005420:Flavoproteins / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D008954:Models, Biological; D010539:Permeability; D010766:Phosphorylation; D013601:T-Lymphocytes / Q000473:pathology* / Q000821:virology*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D003574:Cytochrome c Group; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D005420:Flavoproteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D016159:Tumor Suppressor Protein p53; D020169:Caspases