Human immunodeficiency virus 1 envelope glycoprotein complex-induced apoptosis involves mammalian target. of rapamycin/FKBP12-rapamycin-associated protein-mediated p53 phosphorylation

Syncytia arising from the fusion of cells expressing a lymphotropic human i mmunodeficiency virus (HIV)-1-encoded envelope glycoprotein complex (Env) g ene 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 in sertion of Bax in mitochondrial membranes, subsequent release of cytochrome c, caspase activation, and apoptosis. p53S15 phosphorylation also occurs i n vivo, in HIV-1(+) donors, where it can be detected in preapoptotic and ap optotic syncytia in lymph nodes, as well as in peripheral blood mononuclear cells, correlating with viral load. Syncytium-induced p53S15 phosphorylati on is mediated by the upregulation/activation of mammalian target of rapamy cin (mTOR), also called FKBP12-rapamycin-associated protein (FRAP), which c oimmunoprecipitates with p53. Inhibition of mTOR/FRAP by rapamycin reduces apoptosis in several paradigms of syncytium-dependent death, including in p rimary CD4(+) lymphoblasts infected by HIV-1. Concomitantly, rapamycin inhi bits p53S15 phosphorylation, mitochondrial translocation of Bax, loss of th e mitochondrial transmembrane potential, mitochondrial release of cytochrom e c, and nuclear chromatin condensation. Transfection with dominant negativ e 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.