4th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 22-25 September 2002, San Diego, CA, USA

HIV PROTEASE INHIBITORS PROMOTE ATHEROSCLEROTIC LESION FORMATION INDEPENDENT OF DYSLIPIDAEMIA BY INCREASING CD36-DEPENDENT CHOLESTEROL ACCUMULATION IN MACROPHAGES

Antiviral Therapy 2002; 7:L7 (abstract 11)

J Dressman, J Kincer, SV Matveev, L Guo, RN Greenberg, T Guerin, D Meade, XA Li, W Zhu, A Uittenbogaard, ME Wilson and EJ Smart
University of Kentucky School of Medicine, Lexington, Ky., USA

OBJECTIVES: These studies use both in vitro and in vivo models to determine if HIV protease inhibitors induce a specific increase in macrophage CD36 levels, macrophage cholesterol levels, and the formation of atherosclerotic lesions.

METHODS/RESULTS: Because one of the prominent features of atherosclerotic lesions is the presence of lipid-laden macrophages we determined if HIV protease inhibitors could directly affect the amount of cellular cholesterol associated with macrophages. To test this, THP-1 cells, a model human monocyte/macrophage cell line, were differentiated to macrophages and then incubated in the presence of 30 ng/ml of amprenavir, indinavir, or ritonavir for 24 h. Surprisingly, incubation of THP-1 cells with amprenavir, indinavir, or ritonavir caused the up-regulation of the scavenger receptor, CD36, and the accumulation of cholesterol. The use of CD36 blocking antibodies demonstrated that HIV protease inhibitor-induced increases in THP-1 cellular cholesterol were dependent on CD36. These data led to the hypothesis that HIV protease inhibitors induce foam cell formation and consequently atherosclerotic lesions by up-regulating CD36 and cholesterol accumulation independent of dyslipidaemia. The in vitro data established that HIV protease inhibitors increase the cellular level of macrophage cholesterol in a CD36-dependent manner. These data implied that frank dyslipidaemia is not necessary to generate lipid-laden macrophages and subsequently atherosclerotic lesions. To directly test this prediction two doses of amprenavir, indinavir, or ritonavir were given to LDLR null mice in the drinking water for 0, 4, or 8 weeks. The studies with LDLR null mice demonstrated that low doses of amprenavir, indinavir, and ritonavir induce an increase in the level of CD36 and cholesterol in peritoneal macrophages and the development of significant atherosclerotic lesions without altering plasma lipids. Finally, mice lacking CD36 were protected from protease inhibitor-induced atherosclerotic lesion formation.

CONCLUSION: We conclude that HIV protease inhibitors contribute to the formation of atherosclerotic lesions by promoting the up-regulation of CD36 and the accumulation of sterol in macrophage.

Presenting author: EJ Smart

2002-09-22
11

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