Background:  The HIV protease inhibitors (PI) are frequently used to treat HIV infection, and have been found to have intrinsic anti-apoptotic properties, independent of their anti-HIV protease effects. We therefore, investigated whether HIV PI would block HIV bystander death in vitro and ex vivo, despite HIV protease resistance.

Methods:  Primary CD4 T cells were isolated from healthy donors, and pre-treated with 7 mM of nelfinavir (NFV) or control. One set of cells was treated with AT-2-inactivated HIV_RF, HIV_RF M46I, L63P, V82T, I84V and HIV_RF V82F I84V (X4), or mock control. Separate primary CD4 T cells, pre-treated with 7 mM of NFV or control, and were incubated with plasma from HIV-infected individuals with viral genotypes that confer NFV resistance that had been pre-treated with AT-2. After 24 hours, the cell were stained for TUNEL and analyzed by flow cytometry.

Results:  Cells treated with either wild type or mutant virus died within 24 hours. The death was significantly inhibited in all cases by NFV treatment (HIV_RF 47%, HIV_RF NFV 8%  p <0.02; HIV_RF M46I, L63P,V82T, I84V control 27%, HIV_RF M46I, L63P,V82T, I84V NFV 2%, p <0.007; HIV_RF V82F I84V control 57%, HIV_RF V82F I84V NFV 10%, p <0.01). Serum from 4 of the 6 HIV-infected patients tested caused primary CD4⁺ T cell death, whereas serum from 2 patients did not. In all cases, death induced by patient serum was significantly blocked (p <0.01) by NFV pre-treatment.

Conclusions:  The HIV PI, NFV, protects primary CD4 T cells from death induced by plasma from HIV-infected patients, even in instances where PI-resistant virus is present.  Together, these results suggest that NFV blocks CD4 T cell death and has a beneficial effect on CD4 T cell survival despite protease inhibitor viral resistance.