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：

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在治疗的HIV疾病中A20上调与肠道上皮细胞的恢复和功能有关

未经治疗的人类免疫缺陷病毒（HIV）感染的特征是肠上皮屏障功能障碍和慢性炎症，相关特征可通过抑制性抗逆转录病毒疗法（ART）减弱至不同程度。HIV疾病和治疗过程中肠上皮细胞（IEC）功能障碍和恢复的特定介体尚未确定。我们研究了通过RNAseq从肠道活检组织中分离的IEC，发现在ART治疗的个体中，泛素修饰酶A20的mRNA水平上调，并且与上皮功能标记（例如CTNNB，CLDN4和TJP1）呈正相关）。在鼠肠类器官模型中，A20表达被干扰素-α（IFNα）抑制，该干扰素在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易于细胞死亡并抑制由干扰素-γ（IFNγ）介导的屏障相关基因，干扰素-γ在未经治疗的感染中也以升高的水平存在。此外，A20特别限制了类器官中IL-17A诱导的炎症基因的表达。最后，用聚乙二醇化的IFNα2a治疗5周的ART抑制的慢性感染个体在外周血单核细胞中显示出A20表达降低。因此，我们的结果与其中增强的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，

试用注册

ClinicalTrials.gov临床试验NCT00594880