title: Mitochondrial membrane hyperpolarization hijacks activated T lymphocytes toward the apoptotic-prone phenotype: homeostatic mechanisms of HIV protease inhibitors.
abstract: A decrease of mitochondrial membrane potential has been hypothesized to be a marker of apoptotic cells, including activated T lymphocytes. It was recently demonstrated that HIV protease inhibitors, independently from any viral infection, can hinder lymphocyte apoptosis by influencing mitochondrial homeostasis. To analyze the mechanisms underlying these effects, a specific study was undertaken in both resting and activated human PBL exposed to either receptor (e.g., anti-Fas)- or nonreceptor (e.g., radiation)-mediated apoptotic stimuli. T cell activation was found to be accompanied by a significant increase in mitochondrial membrane potential, or hyperpolarization, which was undetectable in resting cells. We also detected apoptotic hindering by HIV protease inhibitors only in activated T lymphocytes. This was apparently due to the ability of these drugs to block activation-associated mitochondria hyperpolarization, which, in turn, was paralleled by an impairment of cell cycle progression. Remarkably, protease inhibitors also prevented zidovudine-mediated mitochondrial toxicity. Finally, HIV-infected cells from naive patients behaved identically to activated T cells, displaying hyperpolarized mitochondria, while lymphocytes from patients under highly active antiretroviral therapy (which included HIV protease inhibitors) seemed to react as resting cells. Altogether these results clearly indicate that the hyperpolarization state of mitochondria may represent a prerequisite for the sensitization of lymphocytes to the so-called activation-induced cell death. They also suggest that HIV protease inhibitors, by interfering with induction of the mitochondrial hyperpolarization state, can result in cell survival even independent of any viral infection.
authors.affiliation: Department of Ultrastructures, Istituto Superiore di Sanitá, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Matarrese
authors.forename: Lucrezia
authors.initials: L
authors.lastname: Gambardella
authors.forename: Antonio
authors.initials: A
authors.lastname: Cassone
authors.forename: Stefano
authors.initials: S
authors.lastname: Vella
authors.forename: Roberto
authors.initials: R
authors.lastname: Cauda
authors.forename: Walter
authors.initials: W
authors.lastname: Malorni
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D020169:Caspases / Q000378:metabolism; D002469:Cell Separation; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005260:Female; D017320:HIV Protease Inhibitors / Q000633:toxicity*; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D006706:Homeostasis / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D016130:Immunophenotyping; D019469:Indinavir / Q000633:toxicity; D007399:Interphase / Q000187:drug effects / Q000276:immunology; D007425:Intracellular Membranes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D061466:Lopinavir; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000276:immunology; D008928:Mitochondria / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011744:Pyrimidinones / Q000633:toxicity; D019258:Saquinavir / Q000633:toxicity; D013347:Subcellular Fractions / Q000187:drug effects / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D015215:Zidovudine / Q000633:toxicity
chemical_list: D017320:HIV Protease Inhibitors; D018840:HSP70 Heat-Shock Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011744:Pyrimidinones; D061466:Lopinavir; D015215:Zidovudine; D019469:Indinavir; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D019258:Saquinavir