Reduction of the HIV protease inhibitor-induced ER stress and inflammatory response by raltegravir in macrophages

• Published in: PloS one 2014-03, Vol.9 (3), p.e90856
• Main Authors: Zhang, Xiaoxuan, Cao, Risheng, Liu, Runping, Zhao, Renping, Huang, Yi, Gurley, Emily C, Hylemon, Phillip B, Pandak, William M, Wang, Guangji, Zhang, Luyong, Li, Xiaokun, Zhou, Huiping
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Antiretroviral agents; Antiretroviral drugs; Antiretroviral Therapy, Highly Active - adverse effects; Apoptosis; Atherosclerosis; Biology; Cardiovascular Diseases - chemically induced; Cardiovascular Diseases - prevention & control; Cell activation; Cell Line; Cholesterol; Chromatography; Chromatography, High Pressure Liquid; Complications; Complications and side effects; Cytokines - metabolism; Disease; Drug therapy; Endoplasmic reticulum; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum Stress - drug effects; Enzyme-Linked Immunosorbent Assay; Foams; Gastroenterology; High performance liquid chromatography; Highly active antiretroviral therapy; HIV; HIV infections; HIV Infections - drug therapy; HIV Integrase Inhibitors - adverse effects; HIV Integrase Inhibitors - therapeutic use; HIV Protease Inhibitors - adverse effects; HIV Protease Inhibitors - therapeutic use; Homeostasis; Human immunodeficiency virus; Humans; Immunology; Infection; Inflammation; Inflammation - metabolism; Inflammatory response; Integrase; Interleukin-6 - metabolism; Internal medicine; Kupffer Cells - metabolism; Lipid Metabolism; Lipids; Lipids - chemistry; Liquid chromatography; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Male; Medical research; Medicine; Metabolism; Mice; Mice, Inbred C57BL; Oxidative stress; Penicillin; Pharmaceuticals; Pharmacy; Protease; Protease inhibitors; Proteases; Proteins; Raltegravir Potassium - therapeutic use; Reactive Oxygen Species - metabolism; Rodents; Stress response; Studies; Toxicity; Tumor Necrosis Factor-alpha - metabolism; Veterans
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0090856

HIV protease inhibitor (PI), the core component of highly active antiretroviral treatment (HAART) for HIV infection, has been implicated in HAART-associated cardiovascular complications. Our previous studies have demonstrated that activation of endoplasmic reticulum (ER) stress is linked to HIV PI-induced inflammation and foam cell formation in macrophages. Raltegravir is a first-in-its-class HIV integrase inhibitor, the newest class of anti-HIV agents. We have recently reported that raltegravir has less hepatic toxicity and could prevent HIV PI-induced dysregulation of hepatic lipid metabolism by inhibiting ER stress. However, little information is available as to whether raltegravir would also prevent HIV PI-induced inflammatory response and foam cell formation in macrophages. In this study, we examined the effect of raltegravir on ER stress activation and lipid accumulation in cultured mouse macrophages (J774A.1), primary mouse macrophages, and human THP-1-derived macrophages, and further determined whether the combination of raltegravir with existing HIV PIs would potentially exacerbate or prevent the previously observed activation of inflammatory response and foam cell formation. The results indicated that raltegravir did not induce ER stress and inflammatory response in macrophages. Even more interestingly, HIV PI-induced ER stress, oxidative stress, inflammatory response and foam cell formation were significantly reduced by raltegravir. High performance liquid chromatography (HPLC) analysis further demonstrated that raltegravir did not affect the uptake of HIV PIs in macrophages. Raltegravir could prevent HIV PI-induced inflammatory response and foam cell formation by inhibiting ER stress. These results suggest that incorporation of this HIV integrase inhibitor may reduce the cardiovascular complications associated with current HAART.