Lipid metabolic disorders and atherosclerosis associated with HIV protease inhibitor therapy:

Significant advances have been made in recent years toward reducing the morbidity and mortality of AIDS as a consequence of HIV infection. A most significant advance was the discovery and use of protease inhibitors to limit the maturation of infectious viral particles. Unfortunately, the benefits of HIV protease inhibitors are compromised by their numerous undesirable side effects, including peripheral fat wasting and excessive central fat deposition (lipodystrophy), overt hyperlipidemia, insulin resistance, and premature atherosclerosis. Our laboratory is undertaking the task of identifying the mechanism by which HIV protease inhibitor therapy is associated with these lipid metabolic disorders. Our working hypothesis is that HIV protease inhibitors are effective inhibitors of proteasome-mediated degradation of activated SREBP-1 and –2, the transcription factors associated with fat and cholesterol biosynthesis, and the degradation of apoB, the protein associated with atherogenic lipoproteins. We also postulate that HIV protease inhibitors may also adversely affect glucose metabolism by interfering with insulin signaling pathways responsible for glucose clearance. Results obtained so far have shown that one protease inhibitor, ritonavir, is an avid inhibitor of activated SREBP degradation and also stabilizes apoB. However, another protease inhibitor, indinavir, appears to alter lipid and glucose metabolism by a different mechanism. DNA microarray and proteomics approaches are being used to identify the mechanisms by which differrent protease inhibitors elicit different metabolic responses. Current projects in this area of research include:

1) Using mRNA expression profile and proteomics approach to identify the mechanism by which indinavir adversely affect lipid and glucose metabolic pathways.

2)  Compare and identify abnormalities associated with other HIV protease inhibitors.

3) Determine the potential of interactions between protease inhibitors and viral infection in promoting abnormalities in lipid and glucose metabolism.

Understanding the mechanism(s) by which HIV protease inhibitors adversely affect lipid and glucose metabolism will aid the design of new generations of anti-viral agents without the deleterious effects of lipodystrophy, diabetes, and premature coronary artery disease.