HIV-protease inhibitors (PI) prevent the maturation of nascent virions and are thus very effective in blocking further infection in HIV-positive patients. Significant reductions in mortality from AIDS have been achieved with the use of PI. Cross-sectional studies, however, have suggested accelerated atherosclerosis in HIV-positive patients receiving PI therapy and this may be associated with high prevalence of several risk factors for atherosclerosis: hyperlipidemia, hyperglycemia, insulin resistance and fat redistribution. The exact mechanisms underlying these metabolic changes are not known. Based on homology studies, HIV-protease inhibitors may interfere with the function of the low density lipoprotein receptor-related protein (LRP) and the cytoplasmic retinol binding protein (CRBP). LRP is responsible for the hepatic uptake of intestinal lipoproteins transporting dietary fats and fat- soluble vitamins such as vitamin A. Inside the cell, the transport of retinoic acid by CRBP may interact with peroxisome proliferator activator receptor (PPAR) and thus affect the production of apoC-III and the differ- entiation of adipocytes. Using non-radioactive tracers, we propose to examine the changes in lipoprotein metabolism associated with HIV infection and the therapeutic use of PI. The metabolism of oral retinol will be examined with respect to the effect of PI on LRP. The production of apoC-III, a PPAR- regulated apolipoprotein linked to hypertriglyceridemia and diabetes, will be examined with respect to its association in PI-induced hypertriglyceridemia. While hyperlipidemia may be associated with atherosclerosis, it cannot explain the accelerated progression of the disease. Changes in physiological and biochemical responses with oxidative stress associated with postprandial lipemia will be examined as a possible mechanism for accelerated disease progression. A comprehensive longitudinal study with new markers for CAD will also be conducted to characterize the progression of the risk factors with PI. In a subset of patients with hyperlipidemia, the efficacy of combined therapy with vitamin A, fibrates, and thiazoladinediones will be evaluated. These are specific agents that are effective in reducing triglyceride as well as improving insulin resistance.
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