HIV protease inhibitors prevent mitochondrial hyperpolarization and redox imbalance and decrease endogenous uncoupler protein-2 expression in gp 120-activated human T lymphocytes.
It has been demonstrated that HIV protease inhibitors (Pls) are able to inhibit apoptosis of both infected and uninfected T cells. It was hypothesized that the mechanisms underlying this effect are associated with a specific activity of these drugs against mitochondrial modifications occurring in the execution phase of apoptosis. In this work, we investigated the activity of PIs towards the early changes occurring in mitochondrial membrane potential in freshly isolated uninfected human T lymphocytes sensitized to CD95/Fas-induced physiological apoptosis via pre-exposure to HIV envelope protein gp120. The results obtained clearly indicate that PIs are capable of hindering early morphogenetic changes bolstering T cell apoptosis, that is, cell polarization and mitochondrial hyperpolarization. The target effect on mitochondria appeared to be characterized by a specific activity of Pls in the maintenance of their homeostasis either in intact cells or in cell-free systems, that is, isolated mitochondria. Pls seem to act as boosters of mitochondrial defense mechanisms, including modulation of endogenous uncouplers. These results add new insights in the field of PI mitochondrial toxicity mechanisms and pharmacological perspectives for the use of these drugs in the control of immune system homeostasis.
Matarrese
Paola
P
Department of Drug Research and Evaluation, Istituto Superiore di Sanitá, viale Regina Elena 299-00161 Rome, Italy.
Tinari
Antonella
A
Gambardella
Lucrezia
L
Mormone
Elisabetta
E
Narilli
Piero
P
Pierdominici
Marina
M
Cauda
Roberto
R
Malorni
Walter
W
D017209:Apoptosis / Q000187:drug effects; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000502:physiology; D016764:Cell Polarity; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology*; D017320:HIV Protease Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D006801:Humans; D019469:Indinavir; D007473:Ion Channels; D008213:Lymphocyte Activation / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D026901:Membrane Transport Proteins / Q000032:analysis*; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D024101:Mitochondrial Proteins / Q000032:analysis*; D010084:Oxidation-Reduction; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D000071246:Uncoupling Protein 2; D019014:fas Receptor / Q000502:physiology
D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; D015699:HIV Envelope Protein gp120; D017320:HIV Protease Inhibitors; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D000071246:Uncoupling Protein 2; D019014:fas Receptor; D019469:Indinavir