Reduction of the HIV Protease Inhibitor-Induced ER Stress and Inflammatory Response by Raltegravir in Macrophages

Background 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. Methodology and Principal Findings 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. Conclusion and Significance 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.

[1]  M. Bertrand,et al.  The unfolded protein response at the crossroads of cellular life and death during endoplasmic reticulum stress , 2012, Biology of the cell.

[2]  Huiping Zhou.  HIV protease inhibitors induce endoplasmic reticulum stress and disrupt barrier integrity in intestinal epithelial cells. , 2011, Methods in enzymology.

[3]  L. Baki,et al.  HIV protease inhibitors elicit volume-sensitive Cl- current in cardiac myocytes via mitochondrial ROS. , 2010, Journal of molecular and cellular cardiology.

[4]  L. Rossoni,et al.  Oxidative stress and inflammatory mediators contribute to endothelial dysfunction in high-fat diet-induced obesity in mice , 2010, Journal of hypertension.

[5]  P. Hylemon,et al.  Prevention of HIV Protease Inhibitor-Induced Dysregulation of Hepatic Lipid Metabolism by Raltegravir via Endoplasmic Reticulum Stress Signaling Pathways , 2010, Journal of Pharmacology and Experimental Therapeutics.

[6]  A. Curran,et al.  Raltegravir, Etravirine, and Ritonavir-Boosted Darunavir: A Safe and Successful Rescue Regimen for Multidrug-Resistant HIV-1 Infection , 2009, Journal of acquired immune deficiency syndromes.

[7]  C. Hughes,et al.  New antiretroviral drugs: a review of the efficacy, safety, pharmacokinetics, and resistance profile of tipranavir, darunavir, etravirine, rilpivirine, maraviroc, and raltegravir , 2009, Expert opinion on pharmacotherapy.

[8]  C. Tsioufis,et al.  Oxidative stress and inflammatory process in patients with atrial fibrillation: the role of left atrium distension. , 2009, International journal of cardiology.

[9]  Lixin Sun,et al.  HIV protease inhibitor lopinavir-induced TNF-alpha and IL-6 expression is coupled to the unfolded protein response and ERK signaling pathways in macrophages. , 2009, Biochemical pharmacology.

[10]  M. Czaja,et al.  Autophagy regulates lipid metabolism , 2009, Nature.

[11]  C. Tincati,et al.  Microbial translocation is associated with sustained failure in CD4+ T-cell reconstitution in HIV-infected patients on long-term highly active antiretroviral therapy , 2008, AIDS.

[12]  B. Dong,et al.  Raltegravir: the first HIV integrase inhibitor. , 2008, Clinical therapeutics.

[13]  D. Eizirik,et al.  An update on lipotoxic endoplasmic reticulum stress in pancreatic beta-cells. , 2008, Biochemical Society transactions.

[14]  D. Hazuda,et al.  Raltegravir with optimized background therapy for resistant HIV-1 infection. , 2008, The New England journal of medicine.

[15]  Ming Yan,et al.  Prevention of free fatty acid–induced hepatic lipotoxicity by 18β‐glycyrrhetinic acid through lysosomal and mitochondrial pathways , 2008, Hepatology.

[16]  J. Poirier,et al.  Quantification of the HIV-integrase inhibitor raltegravir (MK-0518) in human plasma by high-performance liquid chromatography with fluorescence detection. , 2008, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[17]  N. Kaplowitz,et al.  Endoplasmic reticulum stress and liver injury. , 2007, Seminars in liver disease.

[18]  T. Zou,et al.  HIV protease inhibitors increase TNF-α and IL-6 expression in macrophages: Involvement of the RNA-binding protein HuR , 2007 .

[19]  T. Ravikumar,et al.  Pro-inflammatory cytokines from Kupffer cells downregulate hepatocyte expression of adrenomedullin binding protein-1. , 2007, Biochimica et biophysica acta.

[20]  V. Nair,et al.  HIV integrase inhibitors as therapeutic agents in AIDS , 2007, Reviews in medical virology.

[21]  S. Bennett,et al.  HIV protease inhibitors modulate apoptosis signaling in vitro and in vivo , 2007, Apoptosis.

[22]  P. Hylemon,et al.  HIV protease inhibitors activate the unfolded protein response and disrupt lipid metabolism in primary hepatocytes. , 2006, American journal of physiology. Gastrointestinal and liver physiology.

[23]  N. Kaplowitz,et al.  Unfolding new mechanisms of alcoholic liver disease in the endoplasmic reticulum , 2006, Journal of gastroenterology and hepatology.

[24]  D. Ron,et al.  Endoplasmic reticulum stress signaling in disease. , 2006, Physiological reviews.

[25]  R. Kaufman,et al.  The unfolded protein response , 2006, Neurology.

[26]  A. Spector.  HIV protease inhibitors and hyperlipidemia: a fatty acid connection. , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[27]  P. Hylemon,et al.  HIV Protease Inhibitors Activate the Unfolded Protein Response in Macrophages: Implication for Atherosclerosis and Cardiovascular Disease , 2005, Molecular Pharmacology.

[28]  S. Basu,et al.  Oxidative stress and inflammatory response during and following coronary interventions for acute myocardial infarction , 2005, Free radical research.

[29]  George Kuriakose,et al.  The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages , 2003, Nature Cell Biology.

[30]  C. Nichols,et al.  HIV protease inhibitors acutely impair glucose-stimulated insulin release. , 2003, Diabetes.

[31]  Jianglin Fan,et al.  Inflammatory reactions in the pathogenesis of atherosclerosis. , 2003, Journal of atherosclerosis and thrombosis.

[32]  G. Moyle,et al.  HIV-associated lipodystrophy, metabolic complications, and antiretroviral toxicities. , 2002, HIV clinical trials.

[33]  C. Fichtenbaum,et al.  HIV Protease Inhibitor Induces Fatty Acid and Sterol Biosynthesis in Liver and Adipose Tissues Due to the Accumulation of Activated Sterol Regulatory Element-binding Proteins in the Nucleus* , 2001, The Journal of Biological Chemistry.

[34]  V. Mooser,et al.  Antiretroviral therapy-associated hyperlipidaemia in HIV disease , 2001, Current opinion in lipidology.