PATHOGENESIS OF HIV-1-PROTEASE INHIBITOR-ASSOCIATED PERIPHERAL LIPODYSTROPHY, HYPERLIPIDEMIA, AND INSULIN-RESISTANCE

HIV-1 protease-inhibitor treatments are associated with a syndrome of peripheral lipodystrophy, central adiposity, breast hypertrophy in wom en, hyperlipidaemia, and insulin resistance. The catalytic region of H IV-1 protease, to which protease inhibitors bind, has approximately 60 % homology to regions within two proteins that regulate lipid metaboli sm: cytoplasmic retinoic-acid binding protein type 1 (CRABP-1) and low density lipoprotein-receptor-related protein (LRP). We hypothesise th at protease inhibitors inhibit CRABP-1-modified, and cytochrome P450 3 A-mediated synthesis of cis-9-retinoic acid, a key activator of the re tinoid X receptor; and peroxisome proliferator activated receptor type gamma (PPAR-gamma) heterodimer, an adipocyte receptor that regulates peripheral adipocyte differentiation and apoptosis. Protease-inhibitor binding to LRP would Impair hepatic chylomicron uptake and triglyceri de clearance by the endothelial LRP-lipoprotein lipase complex. The re sulting hyperlipidaemia contributes to central fat deposition (and in the breasts in the presence of oestrogen), insulin resistance, and, in susceptible individuals, type 2 diabetes. Understanding the syndrome' s pathogenesis should lead to treatment strategies and to the design o f protease inhibitors that do not cause this syndrome.