HIV-1 Coinfection and Morphine Coexposure Severely Dysregulate Hepatitis C Virus-Induced Hepatic Proinflammatory Cytokine Release and Free Radical Production: Increased Pathogenesis Coincides with Uncoordinated Host Defenses
HIV-1 Coinfection and Morphine Coexposure Severely Dysregulate Hepatitis C Virus-Induced Hepatic Proinflammatory Cytokine Release and Free Radical Production: Increased Pathogenesis Coincides with Uncoordinated Host Defenses
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DOI：
10.1128/jvi.05239-11
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发表时间：
2011-11-01
影响因子：
5.4
通讯作者：
Hauser, Kurt F.
中科院分区：
文献类型：
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作者：
El-Hage, Nazira;Dever, Seth M.;Hauser, Kurt F.
1 型人类免疫缺陷病毒 (HIV-1) 和丙型肝炎病毒 (HCV) 的混合感染是一个全球性问题，在注射吸毒者中更为普遍，因为他们感染这两种病毒的风险较高。在同时感染 HIV-1 和 HCV 的人肝细胞中检查了炎症细胞因子和氧化应激的作用。使用吗啡（海洛因的生物活性产物）、HIV-1 Tat 和 MN 株 gp120 (gp120(MN)) 蛋白以及 X4 HIV-1(LAI/IIIB) 和 R5 HIV-1(SF162) 分离株来研究 HCV (JFH1) 感染的 Huh7.5.1 细胞群的疾病进展机制。 HCV 增加 Huh7.5.1 细胞中肿瘤坏死因子-α (TNF-α) 和白细胞介素 6 (IL-6) 的释放，并增加活性氧 (ROS)、一氧化氮 (NO) 和 3-硝基酪氨酸 (3-NT) 的产生。吗啡优先影响R5 向性的HIV-1 与Huh7.5.1 细胞的相互作用，但不影响X4 向性的相互作用。 HIV-1蛋白或分离物增加HCV感染细胞中细胞因子的释放，而向共感染细胞添加吗啡会导致复杂的失衡，根据细胞因子、吗啡浓度、暴露持续时间和所涉及的特定病原体，显着扰乱细胞因子分泌。在 HCV 和 HIV-1 共暴露的细胞中，ROS、NO 和 3-NT 的产生显着增加，而暴露于吗啡则进一步增加了 ROS。蛋白酶体抑制剂 MG132 显着降低氧自由基、细胞因子水平和 HCV 蛋白水平。我们的研究结果表明，同时接触 HCV 和 HIV-1 会加剧肝脏炎症，泛素蛋白酶体系统和 NF-κ B 是反应的关键方面，吗啡进一步加剧了宿主防御的破坏。结果表明，阿片类药物滥用和 HIV-1 合并感染都会通过免疫防御失调进一步加速 HCV 介导的肝病。
Coinfection with human immunodeficiency virus type-1 (HIV-1) and hepatitis C virus (HCV) is a global problem that is more prevalent in injection drug users because they have a higher risk for acquiring both viruses. The roles of inflammatory cytokines and oxidative stress were examined in HIV-1- and HCV-coinfected human hepatic cells. Morphine (the bioactive product of heroin), HIV-1 Tat and the MN strain gp120 (gp120(MN)) proteins, and X4 HIV-1(LAI/IIIB) and R5 HIV-1(SF162) isolates were used to study the mechanisms of disease progression in HCV (JFH1)-infected Huh7.5.1 cell populations. HCV increased tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) release and augmented production of reactive oxygen species (ROS), nitric oxide (NO), and 3-nitrotyrosine (3-NT) in Huh7.5.1 cells. Morphine preferentially affected R5-tropic, but not X4-tropic, HIV-1 interactions with Huh7.5.1 cells. HIV-1 proteins or isolates increased cytokine release in HCV-infected cells, while adding morphine to coinfected cells caused complex imbalances, significantly disrupting cytokine secretion depending on the cytokine, morphine concentration, exposure duration, and particular pathogen involved. Production of ROS, NO, and 3-NT increased significantly in HCV- and HIV-1-coexposed cells while exposure to morphine further increased ROS. The proteasome inhibitor MG132 significantly decreased oxyradicals, cytokine levels, and HCV protein levels. Our findings indicate that hepatic inflammation is increased by combined exposure to HCV and HIV-1, that the ubiquitin-proteasome system and NF-kappa B contribute to key aspects of the response, and that morphine further exacerbates the disruption of host defenses. The results suggest that opioid abuse and HIV-1 coinfection each further accelerate HCV-mediated liver disease by dysregulating immune defenses.