Progressive Proximal-to-Distal Reduction in Expression of the Tight Junction Complex in Colonic Epithelium of Virally-Suppressed HIV plus Individuals
Progressive Proximal-to-Distal Reduction in Expression of the Tight Junction Complex in Colonic Epithelium of Virally-Suppressed HIV plus Individuals
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DOI：
10.1371/journal.ppat.1004198
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发表时间：
2014-06-01
期刊：
影响因子：
6.7
通讯作者：
Levine, Alan D.
中科院分区：
文献类型：
--
作者：
Chung, Charlotte Y.;Alden, Stephanie L.;Levine, Alan D.
有效的抗逆转录病毒疗法（ART）可显著减少艾滋病相关并发症，但长期接受ART治疗的艾滋病毒感染患者的预期寿命与未感染对照组相比仍然缩短，这是由于非艾滋病相关发病率的风险增加。许多人认为这些并发症是由肠道易位的微生物产物引起的，这些微生物产物刺激全身性炎症-这是该人群中持续存在的肠道细胞旁通透性增加的结果。假设并发的肠道免疫缺陷和结构屏障恶化驱动微生物易位，并且在未经治疗的致病性SIV感染恒河猴中已经报道了肠上皮破裂的直接证据。为了评估和表征病毒抑制的HIV感染患者的上皮细胞损伤程度，我们分析了肠活检组织在细胞和分子水平上的上皮变化。HIV肠道中的肠上皮大体上是完整的，肠上皮细胞的相对丰度和包装没有减少。我们没有发现肠上皮紧密连接（TJ）的结构和亚细胞定位变化的证据，但观察到结肠，但不是末端回肠，TJ成分的转录水平在HIV+队列显着下降。HIV阳性患者降结肠中TJ蛋白的减少证实了这一结果。在HIV+队列中，结肠TJ转录水平沿近端至远端轴沿着逐渐降低。相反，在健康对照组中，相同TJ转录物的表达水平从近端到远端肠道保持不变或逐渐增加。非TJ肠上皮细胞特异性mRNA揭示了HIV相关转录改变的不同模式，认为HIV结肠中肠上皮转录调控的总体变化。这些发现表明，持续的肠上皮失调涉及减少TJ表达是一种机制，驱动增加结肠通透性和微生物易位的ART治疗的HIV感染的患者，和一个可能的免疫致病因素的非艾滋病相关的并发症。
Effective antiretroviral therapy (ART) dramatically reduces AIDS-related complications, yet the life expectancy of long-term ART-treated HIV-infected patients remains shortened compared to that of uninfected controls, due to increased risk of non-AIDS related morbidities. Many propose that these complications result from translocated microbial products from the gut that stimulate systemic inflammation - a consequence of increased intestinal paracellular permeability that persists in this population. Concurrent intestinal immunodeficiency and structural barrier deterioration are postulated to drive microbial translocation, and direct evidence of intestinal epithelial breakdown has been reported in untreated pathogenic SIV infection of rhesus macaques. To assess and characterize the extent of epithelial cell damage in virally-suppressed HIV-infected patients, we analyzed intestinal biopsy tissues for changes in the epithelium at the cellular and molecular level. The intestinal epithelium in the HIV gut is grossly intact, exhibiting no decreases in the relative abundance and packing of intestinal epithelial cells. We found no evidence for structural and subcellular localization changes in intestinal epithelial tight junctions (TJ), but observed significant decreases in the colonic, but not terminal ileal, transcript levels of TJ components in the HIV+ cohort. This result is confirmed by a reduction in TJ proteins in the descending colon of HIV+ patients. In the HIV+ cohort, colonic TJ transcript levels progressively decreased along the proximal-to-distal axis. In contrast, expression levels of the same TJ transcripts stayed unchanged, or progressively increased, from the proximal-to-distal gut in the healthy controls. Non-TJ intestinal epithelial cell-specific mRNAs reveal differing patterns of HIV-associated transcriptional alteration, arguing for an overall change in intestinal epithelial transcriptional regulation in the HIV colon. These findings suggest that persistent intestinal epithelial dysregulation involving a reduction in TJ expression is a mechanism driving increases in colonic permeability and microbial translocation in the ART-treated HIV-infected patient, and a possible immunopathogenic factor for non-AIDS related complications.