HIV protease inhibitors promote the development of lipid-laden macrophages, even in the absence of elevated plasma lipids.
Lipid laden macrophages are a key element in the development of the accumulations within the walls of arteries called foam cells that are the precursors to more serious artery damage.
The effect seems to occur because protease inhibitors encourage macrophages to express a protein called CD36 on their surfaces. When CD36 levels are high, macrophages will absorb more cholesterol.
The study, carried out by the University of Kentucky Medical School, and published today in the Journal of Clinical Investigation, was carried out in genetically modified mouse and human cells, and first presented at last year’s Fourth International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV.
The researchers exposed human PBMCs and THP-1 cells (monocyte/macrophage cell line) to amprenavir, indinavir and ritonavir along with LDL cholesterol, and found that when compared with a control sample, cells exposed to protease inhibitors accumulated significantly more cholesterol.
The degree of cholesterol accumulation was correlated with the degree of increase in CD36 expression, with ritonavir the most potent up-regulator of expression and amprenavir the least. A similar pattern was seen in mice, but mice genetically modified to lack the CD36 receptor did not accumulate cholesterol in macrophages when exposed to protease inhibitors.
Mice lacking LDL cholesterol receptors were also exposed to protease inhibitors; at higher PI doses the drugs induced lipid elevations, but lipid levels remained normal at lower doses. However, when macrophages were isolated from mice exposed to lower doses, they were found to contain higher levels of cholesterol compared to a control group.
Finally, mice were exposed to protease inhibitors for eight weeks, and then assessed for the presence of atherosclerotic lesions. The total area of lesions was correlated with the degree of CD36 expression and cholesterol accumulation, with the greatest area of lesions seen in mice exposed to ritonavir. Mice lacking the CD36 receptor that were exposed to ritonavir had no more lesions than control mice after eight weeks.
Human PBMCs were also tested for PPAR-gamma expression, since activation of PPAR-gamma upregulates CD36 expression. In the presence of LDL cholesterol, PBMCs exposed to ritonavir had elevated PPAR-gamma levels, but exposure to ritonavir alone or LDL cholesterol alone did not affect levels.
Importantly, two protein kinase C (PKC) inhibitors were found to inhibit ritonavir-associated increases in PPAR-gamma activity and CD36 expression.
The authors conclude that “caution should be used when monitoring the effects of HIV protease inhibitors in patients because atherosclerosis may be promoted without a corresponding increase in marker plasma lipids. A more useful test may be to screen PBMCs form patients for an increase in CD36.”
Another research group has reached opposing conclusions however. Sharon Walmsley and colleagues in Toronto found that CD36 expression declined in patients treated with lopinavir-containing HAART regimens. In an editorial in this month’s Journal of Clinical Investigation, David Hui of University of Cincinnati College of Medicine suggests that the discrepancy may be down to the nature of the cell lines used to test the effect on CD36. Whilst the Toronto group used human monocytes, the Kentucky group used macrophages. Dr Hui suggests that protease inhibitors may have opposite effects in macropheges and monocytes, and the down-regulation of CD36 on monocytes may explain impaired glucose tolerance, insulin resistance and hyperlipidemia.
“CD36 is a major fatty acid transporter in tissues with high metabolic capacity. Its down-regulation in tissues such as the heart, adipose and skeletal muscle would impair fatty acid utilisation and decrease insulin responsiveness in these tissues, thus resulting in glucose intolerance, insulin resistance and hyperlipidemia. These two effects may act synergistically in promoting premature atherosclerosis”, he comments.”
Further information on this website
Heart disease and HAART - overview of current evidence on cardiovascular disease and anti-HIV treatm,ent, including discussion on other mechanisms by which HAART might cause atherosclerosis.
Dressman J et al. HIV protease inhibitors promote atherosclerotic lesion formation independent of dyslipidemia by increasing CD36-dependent cholesteryl ester accumulation in macrophages. J Clin Invest 111: 389-397, 2003.
Hui DY. HIV protease inhibitors and atherosclerosis. J Clin Invest 111: 317-318, 2003.
Serghides L et al. CD36 deficiency induced by antiretroviral therapy. AIDS 16: 353-358, 2003.