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HIV Protease Inhibitors Activate the Unfolded Protein Response in Macrophages: Implication for Atherosclerosis and Cardiovascular Disease

Department of Microbiology & Immunology (H.Z., P.B.H.), Division of Gastroenterology, Department of Internal Medicine and McGuire Veterans Affairs Medical Center (W.M.P.), Department of Physiology (V.L.), and Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine (R.N.), Virginia Commonwealth University, Richmond, Virginia

Human immunodeficiency virus (HIV) protease inhibitors have been successfully used in highly active antiretroviral therapy for HIV-1 infection. Treatment of patients infected with HIV with HIV protease inhibitors is unfortunately associated with a number of clinically significant metabolic abnormalities and an increased risk of premature atherosclerosis and myocardial infarction. However, the cellular/molecular mechanisms of the HIV protease inhibitor-induced lipid dysregulation and atherosclerosis remain elusive. Macrophages are the most prominent cell type present in atherosclerotic lesions and play essential roles in both early lesion development and late lesion complications. In this study, we demonstrate that three different HIV protease inhibitors (ritonavir, indinavir, and atazanavir) induce endoplasmic reticulum stress and activate the unfolded protein response in mouse macrophages. Furthermore, at therapeutic concentrations (5-15 µM), these HIV protease inhibitors were found to increase the levels of transcriptionally active sterol regulatory element binding proteins, decrease endogenous cholesterol esterification, cause the accumulation of free cholesterol in intracellular membranes, deplete endoplasmic reticulum calcium stores, activate caspase-12, and increase apoptosis in macrophages. These findings provide possible cellular mechanisms by which HIV protease inhibitors promote atherosclerosis and cardiovascular disease in HIV-1 infected patients treated with HIV protease inhibitors.

Address correspondence to: Dr. Phillip B. Hylemon, Department of Microbiology and Immunology, Virginia Commonwealth University, P.O. Box 980678, Richmond, VA 23298-0678. E-mail: hylemon{at}hsc.vcu.edu

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