Highly active anti-retroviral therapy with protease inhibitors has had profound effects on patients infected with HIV, changing HIV infection from a subacute lethal to a chronic ambulatory disease. As such, one of the more deleterious side effects of HIV protease inhibitor therapy is the development of dyslipidemia. With the development of the novel HIV integrase inhibitor raltegravir, Cao et al. sought to demonstrate that this first-in-class intergrase inhibitor would not cause metabolic syndromes as do the current HIV protease inhibitors. HIV protease inhibitor therapy induces endoplasmic reticulum (ER) stress, activating the unfolded protein response, which is an important signaling pathway in HIV protease inhibitor-induced metabolic syndromes such as dyslipidemia. Raltegravir did not induce ER stress or disrupt lipid metabolism in vitro or in vivo. However, raltegravir significantly inhibited the HIV protease inhibitor-induced ER stress and dyslipidemia both in vitro and in vivo without affecting the uptake or metabolism of the HIV protease inhibitor in hepatocytes. These studies suggest that HIV integrase inhibitors may be useful not only for inhibiting HIV but also for treating dyslipidemia induced by chronic HIV protease inhibitor therapy.
See article at J Pharmacol Exp Ther 2010, 334:530–539.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics