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

Xiaoxuan Zhang,Renping Zhao,Phillip B Hylemon,Risheng Cao,Runping Liu,Luyong Zhang,William M Pandak,Emily C Gurley,Xiaokun Li,Huiping Zhou,Yi Huang,Guangji Wang,Yanqiao Zhang

doi:10.1371/journal.pone.0090856

Abstract

BackgroundHIV 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 FindingsIn 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 SignificanceRaltegravir 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.

Highlights

The development of HIV protease inhibitors (HIV PIs) is one of the most significant advances of the past two decades in controlling HIV infection
Raltegravir could prevent HIV PI-induced inflammatory response and foam cell formation by inhibiting endoplasmic reticulum (ER) stress. These results suggest that incorporation of this HIV integrase inhibitor may reduce the cardiovascular complications associated with current highly active antiretroviral treatment (HAART)
Uptake of Raltegravir in Macrophages In order to study the effect of raltegravir on HIV PI-induced inflammation and dysregulation of lipid metabolism in macrophages, we first examined the uptake of raltegravir in macrophages

Summary

Introduction

The development of HIV protease inhibitors (HIV PIs) is one of the most significant advances of the past two decades in controlling HIV infection. Our previous in vitro studies have demonstrated that most HIV PIs induce the accumulation of intracellular free cholesterol and lipid and activate the UPR in hepatocytes and macrophages, but they increase the release of inflammatory cytokines, promote foam cell formation and induce cell apoptosis in macrophages [5,6]. 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. Little information is available as to whether raltegravir would prevent HIV PI-induced inflammatory response and foam cell formation in macrophages

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Results

Discussion

Conclusion