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

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.

Didehydro-Cortistatin A Inhibits HIV-1 Tat Mediated Neuroinflammation and Prevents Potentiation of Cocaine Reward in Tat Transgenic Mice

“…Raltegravir, used as negative control, had no significant impact on IL-1β; however, even if not significantly, it seemed to mediate a decreased in the expression of TNF-α. This effect of Raltegravir on TNF-α expression had been previously reported [74, 75]. The down-modulation of MCP-1 expression by Tat was potently counteracted by dCA but not affected by Raltegravir (Figure 6E).…”

HIV-1–Associated Atherosclerosis

“…HIV ART induces ER stress, increases the synthesis of inflammatory cytokines, including tumor necrosis factor alpha (TNF-α) and IL-6, significantly increases apoptosis, and promotes foam cell formation in macrophages (82). The integrase inhibitor raltegravir can prevent the HIV protease inhibitor–induced inflammatory response and foam cell formation by inhibiting ER stress, suggesting that incorporation of raltegravir may reduce the ER stress-induced CVD associated with current ART (83). …”

An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

“…Emerging evidence now demonstrates direct neurotoxic effects of ART drugs. Nucleoside reverse transcriptase inhibitors have been reported to reduce neuronal axon length [79, 80] and mitochondrial DNA content [81, 82]. Recently, efavirenz which was found to promote amyloid-β (Aβ) production in vitro and in vivo [83], abrogate neural stem cell proliferation [84],and alter mitochondrial dynamics(i.e., increased mitochondrial depolarization, decreased mitochondrial DNA, and altered mitochondrial respiratory function) [81, 85, 86].…”

“…Based on neuropathological data [11, 205], genetic screening [206, 207], and CSF markers [208], researchers have raised the possibility that AD may be becoming more common in HIV patients on cART. Although the exact mechanisms through which cART contributes to Aβ deposition in the brain are unknown, neurotoxic effects of ART drugs such as mitochondrial dysfunction [81, 91, 209], increased oxidative and ER stress [82, 92, 93, 210, 211], and neuronal damage and synaptic loss [212, 213] are now linked to altered AβPP processing and Aβ deposition in the brains of HIV patients.…”