Inhibition of TNF-alpha mediated cell death by HIV-1 specific protease inhibitors.
HIV-1 protease inhibitors have contributed significantly to the reduction in morbidity and mortality associated with HIV-1 disease. Some of their clinical benefit may be attributed to inhibition of non-viral pathogen proteases and mammalian proteases involved in apoptosis. Our objective was to investigate the effect of HIV-1 protease inhibitors on two different mechanisms of apoptosis in cells not exposed to HIV-1. Modulation of apoptosis induced in U937 or Jurkat cells by CD95 (Fas-ligand) or TNF-alpha was measured using flow cytometry using the 7-AAD and annexin/propidium iodide methods. - HIV-1 protease inhibitors reduced TNF-alpha mediated cell death in a dose-dependent manner, with a maximum inhibition ranging between 38% and 60% observed for 100 microM indinavir. Saquinavir and ritonavir, but not nelfinavir also inhibited TNF-alpha induced cell death. Nevirapine (an HIV-1 reverse transcriptase inhibitor) showed no effect. The TNF-alpha activity was also inhibited by the caspase inhibitors Z-VAD-fmk at concentrations of 10 microM or less, and by DEVD-cmk. In contrast, HIV-1 protease inhibitors did not affect CD95 induced apoptosis in Jurkat cells at any of the concentrations tested. Our findings indicate that HIV-1 protease inhibitors may act on mammalian proteases involved in the regulation of apoptosis; whether this is relevant in the clinical setting remains to be established. Identification of the pathways involved may lead to a better understanding of the clinical impact of this drug class and their role in HAART associated toxicities.
Wolf
Timo
T
Klinikum der JW Goethe Universität, Zentrum der Inneren Medizin, Abteilung für Infektiologie, Haus 33, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany. timo.wolf@arcor.de
Findhammer
S
S
Nolte
B
B
Helm
E B
EB
Brodt
H R
HR
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D004347:Drug Interactions; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D019469:Indinavir / Q000494:pharmacology*; D019169:Jurkat Cells; D019888:Nelfinavir / Q000494:pharmacology; D019438:Ritonavir / Q000494:pharmacology; D019258:Saquinavir / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D020298:U937 Cells; D019014:fas Receptor / Q000494:pharmacology
D000970:Antineoplastic Agents; D017320:HIV Protease Inhibitors; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D019469:Indinavir; D019888:Nelfinavir; D019258:Saquinavir; D019438:Ritonavir