Stimulation of vitamin A(1) acid signaling by the HIV protease inhibitor indinavir

HIV protease inhibitors (PIs) are effective drugs for the treatment of AIDS . However, PI therapy is sometimes associated with side-effects including i ncreased plasma lipids and altered body fat distribution, although fat redi stribution may occur in some patients not treated with PIs. Overdosage with vitamin A, acid (all-trans-retinoic acid, ATRA) or its metabolites may cau se similar changes in lipid metabolism Moreover, the PI indinavir and retin oids have been associated with nail, skin, and hair defects, suggesting tha t indinavir and retinoids may exert their effects through similar molecular mechanisms. This hypothesis was tested by examining the effects of PIs on retinoid signaling in vitro. Mesenchymal stem cells (C3H10T1/2) were cultur ed in the presence of various PIs (amprenavir, indinavir, nelfinavir, riton avir, and saquinavir) and synthetic retinoids, and the metabolic response w as assessed by measuring the activity of a retinoid-regulated protein, alka line phosphatase (ALP). Of the PIs tested, only indinavir stimulated ATRA-d ependent ALP activity and altered stem cell morphology; the effects of indi navir occurred in the presence of ATRA, but not in its absence. Moreover, i ndinavir increased the effects of ATRA on lipid accumulation during far cel l differentiation. AGN 193109 (4-[[5,6-dihydro-5,5-dimethyl-8-(4-methylphen yl)-2-naphthalenyl]ethynyl]-benzoic acid), a retinoic acid receptor (RAR) a ntagonist, inhibited the synergistic effects of indinavir and ATRA, indicat ing that indinavir increases RAR signaling. However, indinavir did not pote ntiate ALP activity in the presence of the RAR agonist CH55 (3,5-di-tert-bu tylchalcone 4'-carboxylic acid). Unlike ATRA, CH55 does nor bind to cytosol ic retinoic acid binding protein (CRABP), suggesting that CRABP may regulat e the effects of indinavir on RAR signaling. These observations support the proposal that altered retinoid signaling promotes some of the adverse reac tions associated with indinavir therapy, such as altered lipid metabolism. (C) 2000 Elsevier Science Inc.