Background:  We previously demonstrated that HIV protease inhibitors (PI) induced the formation of atherosclerotic lesions in apoE and LDL receptor null mice by up-regulating CD36 in macrophages and thereby promoting the formation of foam cells. HIV patients are often treated with both PI and nucleosides; therefore we determined the effects of didanosine on the ability of HIV PI to induce the formation of atherosclerotic lesions. Methods:  LDL receptor null mice were treated with amprenavir, indinavir, and ritonavir (25 mg/animal/day) developed atherosclerotic lesions without altering plasma lipids. In contrast, animals treated with vehicle (0.01% ethanol) or didanosine (1 mg/animal/day) did not develop atherosclerotic lesions. Surprisingly, animals treated with both PI and didanosine did not develop atherosclerotic lesions. To determine whether didanosine prevented macrophages from accumulating cholesteryl ester we treated THP-1 cells, a human macrophage-like model, and human peripheral blood monocytes with vehicle, amprenavir, indinavir, ritonavir, didanosine, or with both PI and didanosine.

Results:  Cells treated with PI accumulated cholesteryl esters whereas cells treated with both PI and didanosine did not accumulate cholesteryl ester. We previously demonstrated that PI-induced increases in macrophage sterol levels were caused by the up-regulation of CD36 in a peroxisome proliferating activator receptor (PPAR) and protein kinase C (PKC)-dependent manner. Treatment of macrophages with both PI and didanosine completely inhibited the increase in CD36 protein levels by preventing the up-regulation of PPAR. However, the addition of a direct PPAR activator, ciglitazone, overcame the inhibitory effects of didanosine suggesting that didanosine inhibited upstream of PPAR. PKC activation is necessary for HIV PI-induced PPAR up-regulation, thus we examined the effect of didanosine on PKC. Didanosine induced the down-regulation of PKC.

Conclusions:  We conclude that didanosine prevents HIV protease inhibitor-induced atherosclerotic lesion formation by down regulating PKC which subsequently prevents the up-regulation of PPAR and CD36.

Keywords: CD36; PPAR gamma; PKC