PLoS Pathogens ( IF 5.5 ) Pub Date : 2018-03-05 , DOI: 10.1371/journal.ppat.1006806 Avantika S Chitre 1 , Michael G Kattah 2 , Yenny Y Rosli 2 , Montha Pao 3 , Monika Deswal 3 , Steven G Deeks 3 , Peter W Hunt 1 , Mohamed Abdel-Mohsen 4 , Luis J Montaner 4 , Charles C Kim 1 , Averil Ma 2 , Ma Somsouk 2 , Joseph M McCune 1
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Untreated Human Immunodeficiency Virus (HIV) infection is characterized by intestinal epithelial barrier dysfunction and chronic inflammation, related features that are attenuated to variable degrees by suppressive antiretroviral therapy (ART). Specific mediators of intestinal epithelial cell (IEC) dysfunction and restoration during HIV disease and treatment have yet to be identified. We studied IECs isolated from intestinal biopsies by RNAseq and found that mRNA levels for the ubiquitin-modifying enzyme, A20, are upregulated in ART-treated individuals and are positively correlated with markers of epithelial function (e.g., CTNNB, CLDN4, and TJP1). In a murine intestinal organoid model, A20 expression was suppressed by interferon-alpha (IFNα), which is highly expressed during HIV viremia and induces IFN-mediated signaling. Notably, A20 deletion rendered intestinal organoids more susceptible to cell death and inhibition of barrier-related genes mediated by interferon-gamma (IFNγ), a cytokine also present at elevated levels during untreated infection. Furthermore, A20 specifically restricted expression of IL-17A-induced inflammatory genes in organoids. Finally, ART-suppressed chronically infected individuals treated with pegylated IFNα2a for five weeks demonstrated reduced expression of A20 in peripheral blood mononuclear cells. Our results are thus consistent with a model in which enhanced type I interferons suppress A20 levels, leading to IFNγ-mediated dysfunction. As such, variation in A20 expression during the course of HIV infection could underlie both the development of epithelial dysfunction before the initiation of ART and the recovery of intestinal epithelial integrity thereafter.
Trial registration
ClinicalTrials.gov Clinical Trial NCT00594880
中文翻译：
HIV 疾病治疗期间 A20 上调与肠上皮细胞恢复和功能相关
未经治疗的人类免疫缺陷病毒 (HIV) 感染的特点是肠上皮屏障功能障碍和慢性炎症，而抑制性抗逆转录病毒治疗 (ART) 会不同程度地减弱相关特征。 HIV 疾病和治疗期间肠上皮细胞 (IEC) 功能障碍和恢复的特定介质尚未确定。我们通过 RNAseq 研究了从肠道活检中分离出的 IEC，发现在接受 ART 治疗的个体中，泛素修饰酶 A20 的 mRNA 水平上调，并且与上皮功能标志物（例如CTNNB 、 CLDN4和TJP1 ）呈正相关。在小鼠肠道类器官模型中，A20 表达被干扰素-α (IFNα) 抑制，干扰素-α (IFNα) 在 HIV 病毒血症期间高表达并诱导 IFN 介导的信号传导。值得注意的是，A20 缺失使肠道类器官更容易受到细胞死亡和干扰素γ (IFNγ) 介导的屏障相关基因的抑制的影响，干扰素γ (IFNγ) 是一种细胞因子，在未经治疗的感染期间也以升高的水平存在。此外，A20 特异性限制类器官中 IL-17A 诱导的炎症基因的表达。最后，接受 ART 抑制的慢性感染个体接受聚乙二醇化 IFNα2a 治疗五周，结果显示外周血单核细胞中 A20 的表达降低。因此，我们的结果与增强的 I 型干扰素抑制 A20 水平，导致 IFNγ 介导的功能障碍的模型一致。因此，HIV 感染过程中 A20 表达的变化可能是 ART 开始前上皮功能障碍的发展以及此后肠上皮完整性恢复的基础。
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ClinicalTrials.gov 临床试验 NCT00594880
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