Table 1.

Possible Mechanisms for HIV Protease Inhibitor Mediating Apoptosis

Theories	Evidence
Alter caspase activity	HIV PIs block Fas and TNF mediated apoptosis HIV PIs not block caspase -1, -3, -4, -5, -6, -7, -8, or -9 activity in cell models
Inhibit Calpain activity	HIV PIs inhibit apoptosis in cell systems where calpains are activated HIV PIs blocked m-calpain activation in U937 cells HIV PIs inhibited activity of both m- and -μ calpain isoforms in PC12 cells HIV PI did not inhibit m- or μ-calpain hydrolysis or activation at lower, physiologic, concentrations
Alter levels of apoptosis regulatory proteins	No change in Fas protein levels after HIV PI treatment No change in RNA levels of Fas, Fas L, and TNF after HIV PI treatment No change in Bcl-2, Bax, and Bcl-XL after HIV PI treatment
Maintain Mitochondrial Transmembrane Potential	HIV PIs maintain mitochondrial membrane integrity after apoptosis stimuli HIV PIs prevent cytochrome c release from mitochondria after apoptosis stimuli ANT (adenine nucleotide translocator) necessary for HIV PI to block mitochondria mediated apoptosis