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
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.
Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
PLoS One. 2014 Mar 13;9(3):e90856. doi: 10.1371/journal.pone.0090856. eCollection 2014.
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.
HIV蛋白酶抑制剂（PI）是用于治疗HIV感染的高效抗逆转录病毒疗法（HAART）的核心成分，与HAART相关的心血管并发症有关。我们之前的研究表明，内质网（ER）应激的激活与HIV PI诱导的巨噬细胞炎症和泡沫细胞形成有关。拉替拉韦是同类中的首个HIV整合酶抑制剂，是最新一类抗HIV药物。我们最近报道，拉替拉韦肝毒性较小，并且通过抑制ER应激可预防HIV PI诱导的肝脂质代谢失调。然而，关于拉替拉韦是否也能预防HIV PI诱导的巨噬细胞炎症反应和泡沫细胞形成，几乎没有相关信息。
在本研究中，我们检测了拉替拉韦对培养的小鼠巨噬细胞（J774A.1）、原代小鼠巨噬细胞和人THP-1来源的巨噬细胞中ER应激激活和脂质积累的影响，并进一步确定拉替拉韦与现有HIV PI联合使用是否会加剧或预防之前观察到的炎症反应激活和泡沫细胞形成。结果表明，拉替拉韦不会在巨噬细胞中诱导ER应激和炎症反应。更有趣的是，拉替拉韦显著降低了HIV PI诱导的ER应激、氧化应激、炎症反应和泡沫细胞形成。高效液相色谱（HPLC）分析进一步表明，拉替拉韦不影响巨噬细胞对HIV PI的摄取。
拉替拉韦可通过抑制ER应激预防HIV PI诱导的炎症反应和泡沫细胞形成。这些结果表明，加入这种HIV整合酶抑制剂可能会减少与当前HAART相关的心血管并发症。
