Atherosclerotic cardiovascular disease (ASCVD) is becoming an important cause of morbidity and mortality in HIV-infected persons. Hyperlipidemia is common in HIV-infected persons and protease inhibitors frequently cause or exacerbate hyperlipidemia. Furthermore, it is possible that protease inhibitors may directly promote atherogenesis. Therefore, an understanding of the mechanisms by which protease inhibitors cause hyperlipidemia and whether they directly promote atherogenesis is of great clinical importance. The goals of this proposal are: 1) to determine the physiologic mechanisms by which protease inhibitors therapy causes dyslipidemia in humans using lipoprotein kinetic studies with endogenous labeling of apolipoprotein B with stable isotopes; 2) to determine the molecular mechanisms by which protease inhibitors cause dyslipidemia and may promote atherosclerosis by utilizing """"""""humanized"""""""" mouse models of lipoprotein metabolism and atherosclerosis.
Specific Aim 1 : To test the hypotheses that dyslipidemia associated with protease inhibitor therapy is caused by 1) reduced conversion of VLDL to LDL due to reduced triglyceride lipolysis caused early in susceptible patients by protease inhibitors themselves; 2) increased VLDL apoB production associated subsequently with the development of visceral fat accumulation. Specifically, the investigator will perform lipoprotein kinetic studies using endogenous labeling with stable isotopes in two types of studies in human subjects. Studies will use endogenous labeling with a primed constant infusion of D3- leucine. A compartmental model of apoB-containing lipoprotein metabolism will be constructed and the effect of protease inhibitors on apoB kinetic parameters will be determined. Two types of studies will be performed: a cross-sectional study in HIV patients on PI therapy with lipodystrophy (LD), patients on PI therapy without LD, and patients not on PI therapy without LD as well as control subjects: and a longitudinal study in PI-naive patients who initiate therapy and are studied prior to and twice after initiating therapy. These studies will be performed collaboratively with the other projects in this proposal.
Specific Aim 2 : To use """"""""humanized"""""""" mouse models of lipoprotein metabolism and atherosclerosis to determine the molecular mechanisms by which protease inhibitors cause hyperlipidemia and promote atherosclerosis. Specifically, the investigator will use human apoB transgenic mice and administer protease inhibitors to determine effects on lipoprotein kinetics, lipolytic enzymes and expression of specific lipid-metabolism related genes in liver and adipose to determine those that have been up or down-regulated as a result of protease inhibitor therapy. In order to determine whether protease inhibitors promote atherosclerosis, the investigator will administer protease inhibitors to mice prone to atherosclerosis and determine effects on initiation and progression of atherosclerosis. Finally, the investigator will perform micro array analysis of RNA isolated from the aortic arch (a site that reproducibly develops atherosclerosis) to determine the specific vascular genes that have been up or down-regulated as a result of protease inhibitor therapy. These studies will provide novel insights into the mechanisms of PI-associated dyslipidemia and atherosclerosis.
