title: Reduction of the HIV protease inhibitor-induced ER stress and inflammatory response by raltegravir in macrophages.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, P.R.China; Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Xiaoxuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Risheng
authors.initials: R
authors.lastname: Cao
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, P.R.China; Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Runping
authors.initials: R
authors.lastname: Liu
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, P.R.China.
authors.forename: Renping
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, P.R.China; School of Pharmacy, Wenzhou Medical University, Wenzhou, P.R.China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Gurley
authors.affiliation: Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond, Virginia, United States of America; Department of Internal Medicine/Gastroenterology and McGuire Veterans Affairs Medical Center, Richmond, Virginia, United States of America.
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Hylemon
authors.affiliation: Department of Internal Medicine/Gastroenterology and McGuire Veterans Affairs Medical Center, Richmond, Virginia, United States of America.
authors.forename: William M
authors.initials: WM
authors.lastname: Pandak
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, P.R.China.
authors.forename: Guangji
authors.initials: G
authors.lastname: Wang
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, P.R.China.
authors.forename: Luyong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Wenzhou Medical University, Wenzhou, P.R.China.
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond, Virginia, United States of America; School of Pharmacy, Wenzhou Medical University, Wenzhou, P.R.China; Department of Internal Medicine/Gastroenterology and McGuire Veterans Affairs Medical Center, Richmond, Virginia, United States of America.
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000818:Animals; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000517:prevention & control; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D016207:Cytokines / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D015658:HIV Infections / Q000188:drug therapy*; D019428:HIV Integrase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D017320:HIV Protease Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D006706:Homeostasis; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007728:Kupffer Cells / Q000378:metabolism; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000068898:Raltegravir Potassium / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D019428:HIV Integrase Inhibitors; D017320:HIV Protease Inhibitors; D015850:Interleukin-6; D008055:Lipids; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D000068898:Raltegravir Potassium