1 Department of Immunology, Institute of NeuroImmune Pharmacology, College of Medicine, Florida International University , Miami, Florida.
2 Department of Health Promotion & Disease Prevention, Robert Stempel School of Public Health, Florida International University , Miami, Florida.
Antioxid Redox Signal. 2018 Feb 1;28(4):324-337. doi: 10.1089/ars.2016.6830.
AIMS: Human immunodeficiency virus (HIV) infection induces oxidative stress and alcohol use accelerates disease progression, subsequently causing immune dysfunction. However, HIV and alcohol impact on lipid rafts-mediated immune dysfunction remains unknown. In this study, we investigate the modulation by which oxidative stress induces reactive oxygen species (ROS) affecting redox expression, lipid rafts caveiloin-1, ATP-binding cassette (ABC) transporters, and transcriptional sterol regulatory element-binding protein (SREBP) gene and protein modification and how these mechanisms are associated with arachidonic acid (AA) metabolites in HIV positive alcohol users, and how they escalate immune dysfunction. RESULTS: In both alcohol using HIV-positive human subjects and in vitro studies of alcohol with HIV-1 gp120 protein in peripheral blood mononuclear cells, increased ROS production significantly affected redox expression in glutathione synthetase (GSS), super oxide dismutase (SOD), and glutathione peroxidase (GPx), and subsequently impacted lipid rafts Cav-1, ABC transporters ABCA1, ABCG1, ABCB1, and ABCG4, and SREBP transcription. The increased level of rate-limiting enzyme 3-hydroxy-3-methylglutaryl HMG-CoA reductase (HMGCR), subsequently, inhibited 7-dehydrocholesterol reductase (DHCR-7). Moreover, the expression of cyclooxygenase-2 (COX-2) and lipoxygenase-5 (5-LOX) mRNA and protein modification tentatively increased the levels of prostaglandin E2 synthases (PGE) in plasma when compared with either HIV or alcohol alone. INNOVATION: This article suggests for the first time that the redox inhibition affects lipid rafts, ABC-transporter, and SREBP transcription and modulates AA metabolites, serving as an important intermediate signaling network during immune cell dysfunction in HIV-positive alcohol users. CONCLUSION: These findings indicate that HIV infection induces oxidative stress and redox inhibition, affecting lipid rafts and ABC transports, subsequently upregulating AA metabolites and leading to immune toxicity, and further exacerbation with alcohol use. Antioxid. Redox Signal. 28, 324-337.
目的：人类免疫缺陷病毒（HIV）感染会引起氧化应激，而饮酒会加速疾病进展，从而导致免疫功能障碍。然而，HIV 和酒精对脂筏介导的免疫功能障碍的影响尚不清楚。在这项研究中，我们研究了氧化应激如何通过诱导活性氧（ROS）来影响还原表达、脂筏 Cav-1、ATP 结合盒（ABC）转运体和转录固醇调节元件结合蛋白（SREBP）基因和蛋白质修饰，以及这些机制如何与 HIV 阳性饮酒者中的花生四烯酸（AA）代谢物相关，以及它们如何加剧免疫功能障碍。
结果：在 HIV 阳性饮酒者的人体研究和外周血单核细胞中 HIV-1 gp120 蛋白与酒精的体外研究中，ROS 生成的增加显著影响了谷胱甘肽合成酶（GSS）、超氧化物歧化酶（SOD）和谷胱甘肽过氧化物酶（GPx）的还原表达，进而影响了脂筏 Cav-1、ABC 转运体 ABCA1、ABCG1、ABCB1 和 ABCG4 以及 SREBP 转录。限速酶 3-羟基-3-甲基戊二酰辅酶 A 还原酶（HMGCR）的水平升高，继而抑制了 7-脱氢胆固醇还原酶（DHCR-7）。此外，与单独的 HIV 或酒精相比，环氧化酶-2（COX-2）和脂加氧酶-5（5-LOX）mRNA 和蛋白质修饰的表达水平增加，导致前列腺素 E2 合酶（PGE）在血浆中的水平增加。
创新点：本文首次提出，氧化还原抑制作用影响脂筏、ABC 转运体和 SREBP 转录，并调节 AA 代谢物，作为 HIV 阳性饮酒者免疫细胞功能障碍的重要中间信号网络。
结论：这些发现表明，HIV 感染会引起氧化应激和氧化还原抑制，影响脂筏和 ABC 转运，继而上调 AA 代谢物，导致免疫毒性，并进一步因饮酒而恶化。抗氧化。氧化还原信号。28，324-337。
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