Although highly active anti-retroviral therapy (HAART) has markedly reduced the morbidity and mortality of HIV- infected children, the improved life expectancy is associated with a complex set of metabolic disorders in a subset of patients. These disorders include growth failure with lower lean body mass (LBM) and dyslipidemia, a syndrome characterized by hypertriglyceridemia and hypercholesterolemia. Although the clinical features of these metabolic derangements are described, their mechanistic underpinnings are unknown. It is important to delineate these mechanisms in order to establish new therapies for pediatric patients because growth failure will lead to stunting and chronic dyslipidemia may accelerate the progression to cardiovascular disease in adulthood. In this project we plan to test the following hypotheses: 1) the hypertriglyceridemia of HIV-infected patients with dyslipidemia is the result of an increased rate of very low density lipoprotein (VLDL) synthesis, secondary to a faster rate of lipolysis in the fasted state, and impaired hydrolysis of VLDL- and chylomicron-TG, secondary to impaired lipoprotein lipase activity in the fed state, 2) hypercholesterolemia is in part due to impaired cholesterol transport to the liver because of a reduction in the availability of high density lipoprotein apoprotein Al (HDL-apoAl), 3) a lower fat diet rich in poly and mono- unsaturated fatty acids will improve the hypertriglyceridemia and hypercholesterolemia of HIV-infected dyslipidemic subjects. With respect to protein metabolism we hypothesize that 4) HIV-infected children have a lower LBM due to a deficit in net protein synthesis because of upregulated protein catabolism. To test these hypotheses we propose to conduct stable isotope tracer experiments to achieve the following specific aims:
Specific aim #1. Measure body composition by DEXA, plasma lipid profile, plasma fatty acid appearance rate in the fasted and fed states, fatty acid oxidation, hepatic fatty acid re-esterification, the concentration and synthesis rates of HDL-apoAl, VLDL-TG and - apoB-100, and lipoprotein lipase activity in a group of HIV-infected adolescents with dyslipidemia versus a matched group without dyslipidemia.
Specific aim #2. Compare the effects of a reduced fat diet (28% energy) comprised of a greater proportion of mono- and poly-unsaturated fatty acids versus no dietary modification on these same outcome variables in HIV-infected adolescents with dyslipidemia.
Specific aim #3. Measure lean body mass (LBM) and protein kinetics in HIV-infected prepubertal children versus age-and gender-matched HIV-exposed children and determine the effect of dietary energy and protein supplementation on LBM and protein kinetics in the HIV-infected group. This research may explain why HIV-infected pediatric patients fail to grow normally and why they develop high levels of fat and cholesterol in their blood, which can potentially lead to early heart disease. Knowledge gained from this project may lead to new nutritional therapies to help prevent these conditions. ? ? ? ?
