HIV protease inhibitors promote atherosclerosis independent of dyslipidemia

The development of HIV protease inhibitor (PI)-related atherosclerosis may be a direct consequence of increased accumulation of cholesteryl ester in macrophages, rather than secondary to dyslipidemia. Researchers at the University of Kentucky Medical School report these findings in the 15 January online edition of the Journal of Clinical Investigation.

Dr Eric J Smart and colleagues found that treatment with ritonavir, indinavir or amprenavir increases the level of cholesteryl ester in THP-1 macrophages and peripheral blood mononuclear cells (PBMCs). However, when CD36 blocking antibodies were added or macrophages from CD36 knockout mice were used, the cells failed to accumulate sterol.

Thus, they write, “the increase in CD36 was responsible for the increase in cellular cholesterol.”

The Lexington-based research team confirmed these findings in vivo by adjusting PI dosages to levels that do not cause dyslipidemia in an LDL-receptor-null mouse model or in apoE-null and apoE x CD36 double-null mice.

In the LDLR-null mice and the apoE-null mice, but not in the double-null mice, CD36 protein and cholesteryl ester levels increased in peritoneal macrophages following eight weeks of treatment with PIs.

According to the report, CD36 increased approximately three-fold after treatment amprenavir, five-fold after indinavir, and 13-fold after ritonavir. Furthermore, “the relative increase in the level of CD36…approximated the measured increase in cholesteryl ester accumulation”.

Examination of ascending and descending aortas showed that areas covered by atherosclerotic lesions were significantly larger than in vehicle-treated animals. When PI doses were increased to levels that also caused dyslipidemia, atherosclerosis was further increased, the research team notes.

Based on these findings, Dr Smart’s group cautions that monitoring plasma lipid markers may fail to identify patients on PI therapy at risk for atherosclerosis: “A more useful test may be to screen PBMCs from patients for an increase in CD36.”


J Clin Invest 2003. Doi:10.1172/JCI200316261.

Source: Reuters Health

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