HIV protease inhibitor therapy reverses neutrophil apoptosis in AIDS patients by direct calpain inhibition.
The reduction of neutrophils apoptosis is one of the main non-virological effects of protease inhibitor (PI) therapy. We explore here whether this may be due to the cross-inhibition of calpain, an important non-virological target of PI in vitro. We found that the high basal level of neutrophils apoptosis in AIDS patients is strictly related to an increased intracellular calpain activity. Both alterations disappear after PI treatment, with apoptosis and calpain going back to normal levels after 3 months of PI therapy, independently of a proficient antiviral effect. PI drugs exerted a similar antiapoptotic and anticalpain effects on neutrophils in ex vivo experiments: strikingly, the effects were mimicked by commercially available calpain inhibitors. This study shows, for the first time, that apoptosis of neutrophils in AIDS patients is mediated by calpain, and that neutrophil survival in PI treated AIDS patients is a non virological effect due to calpain inhibition.
Lichtner
M
M
Department of Infectious and Tropical Diseases, La Sapienza University, Viale del Policlinico Roma, 155, 00161, Rome, Italy.
Mengoni
F
F
Mastroianni
C M
CM
Sauzullo
I
I
Rossi
R
R
De Nicola
M
M
Vullo
V
V
Ghibelli
L
L
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D000328:Adult; D000480:Alkynes; D017209:Apoptosis / Q000187:drug effects*; D048588:Benzoxazines; D002154:Calpain / Q000037:antagonists & inhibitors*; D016022:Case-Control Studies; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D003521:Cyclopropanes; D005260:Female; D017320:HIV Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D019469:Indinavir / Q000494:pharmacology / Q000627:therapeutic use; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D009504:Neutrophils / Q000187:drug effects*; D010078:Oxazines / Q000494:pharmacology / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015215:Zidovudine / Q000494:pharmacology / Q000627:therapeutic use
D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D017320:HIV Protease Inhibitors; D010078:Oxazines; D015215:Zidovudine; D019469:Indinavir; C505407:CASP3 protein, human; D002154:Calpain; D053148:Caspase 3; D020169:Caspases; D046988:Proteasome Endopeptidase Complex; C098320:efavirenz