B7 Cosignal Potentiates Apoptosis of Uninfected CD4+ T Lymphocytic Cell Lines Primed by HIV Envelope Proteins

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Abstract
In lymphoid organs, follicular dendritic cells (FDCs), monocytes, and macrophages are targets for HIV infection and reservoirs for infectious virus. Strikingly, the apoptotic cells in these sites are essentially uninfected CD4+ T lymphocytes, but lie in close proximity to infected cells or FDCs carrying trapped HIV virions. To decipher this apoptotic pathway, we have established a two-step experimental system that reproduces in vitro the HIV envelope protein-mediated apoptosis restricted to uninfected CD4+ T lymphocytic cell lines. In this assay, uninfected CD4+ T cell targets undergo apoptosis following an initial priming step on HeLa cells expressing functional HIV envelope proteins at their plasma membrane and a second and necessary stimulation step via the CD3-TCR complex. The CD4+ T lymphocytic cells susceptible to apoptosis are, in contrast, resistant to cell fusion mediated by HIV envelope protein and express SDF-1. FDCs and macrophages are known to be high B7 expressors. Thus in lymph nodes, the cells that have trapped HIV particles in immune complexes at the plasma membrane present both HIV envelope proteins and B7.1 at their surface. We mimicked this situation in vitro by priming CD4+ T lymphocytes on cells expressing the costimulatory molecule B7 in addition to HIV envelope proteins, and show that it resulted in an acceleration and a twofold increase in apoptosis. Finally, we characterized two enzymes, PI3Kinase and PI-PLC, which are both downstream effectors of the CD4 (HIV envelope protein receptor) and CD28 (B7 receptor) activation pathways, and that participated in the early steps of priming for apoptosis.