THE ALTERED PROTEIN METABOLISM OF PEDIATRIC PATIENTS WITH HIV INFECTION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 1a) The hypertriglyceridemia of HIV-infected pediatric patients with the dyslipidemia syndrome is the result of the combined effects of an increased rate of 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 both the fed and fasted states. 1b) The hypercholesterolemia of HIV-infected patients with dyslipidemia is due to impaired reverse transport of cholesterol to the liver because of a reduction in the availability of HDL-apoA1. 2) Consuming a diet of less fat, comprised primarily of unsaturated fatty acids will ameliorate the hypertriglyceridemia and hypercholesterolemia of patients with the dyslipidemia syndrome. 3) Despite an adequate dietary protein intake, HIV-infected children have a lower LBM due to a deficit in the availability of endogenous protein to support LBM synthesis. This decreased protein availability is secondary to a chronic upregulation of protein catabolism relative to intake. We further propose that this condition can be ameliorated by dietary supplementation with more energy and protein. Specific aim #1. Measure body composition, plasma cholesterol and triacylglycerol (TG) concentrations, plasma fatty acid appearance rate in the fasted and fed states (indices of hormone sensitive lipase and lipoprotein lipase activities), fatty acid oxidation, hepatic fatty acid re-esterification, the concentration and synthesis rates of high density lipoprotein apoprotein A1 (HDL-apoA1), very low density lipoprotein TG and apoprotein B-100 (VLDL-TG and -apoB-100) and lipoprotein lipase activity in a group of HIV-infected adolescents with the dyslipidemia syndrome versus an age, gender, disease stage and drug treatment 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 variables in HIV-infected adolescents with dyslipidemia. Specific aim #3. Measure body composition and protein kinetics in prepubertal HIV-infected children versus age and gender matched HIV-exposed children and determine the effect of dietary energy and protein supplementation on protein kinetics in the HIV-infected group of children. 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 A1 (HDL-apoA1), 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-apoA1, VLDL-TG and -apoB-100, and lipoprotein lipase activity in a group of HIV-infected adolescents and young adults 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.