Chung Charlotte Y, Alden Stephanie L, Funderburg Nicholas T, Fu Pingfu, Levine Alan D
Departments of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
PLoS Pathog. 2014 Jun 26;10(6):e1004198. doi: 10.1371/journal.ppat.1004198. eCollection 2014 Jun.
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.
有效的抗逆转录病毒疗法（ART）显著降低了与艾滋病相关的并发症，然而，与未感染的对照组相比，长期接受ART治疗的HIV感染患者的预期寿命仍然缩短，这是由于非艾滋病相关疾病的风险增加。许多人认为，这些并发症是由肠道中易位的微生物产物刺激全身炎症引起的，这是该人群中持续存在的肠道细胞旁通透性增加的结果。肠道免疫缺陷和结构屏障恶化被认为是导致微生物易位的原因，并且在恒河猴未经治疗的致病性SIV感染中已经报道了肠道上皮细胞破坏的直接证据。为了评估和表征病毒抑制的HIV感染患者上皮细胞损伤的程度，我们分析了肠道活检组织在细胞和分子水平上上皮细胞的变化。HIV感染的肠道上皮大体上是完整的，肠道上皮细胞的相对丰度和堆积没有减少。我们没有发现肠道上皮紧密连接（TJ）的结构和亚细胞定位变化的证据，但观察到HIV阳性队列中结肠而非回肠末端TJ成分的转录水平显著降低。HIV阳性患者降结肠中TJ蛋白的减少证实了这一结果。在HIV阳性队列中，结肠TJ转录水平沿近端到远端轴逐渐降低。相比之下，在健康对照组中，相同TJ转录本的表达水平从近端到远端肠道保持不变或逐渐增加。非TJ肠道上皮细胞特异性mRNA揭示了HIV相关转录改变的不同模式，这表明HIV感染的结肠中肠道上皮转录调控发生了总体变化。这些发现表明，持续的肠道上皮失调，包括TJ表达的减少，是导致接受ART治疗的HIV感染患者结肠通透性增加和微生物易位的机制，也是非艾滋病相关并发症的一个可能的免疫致病因素。
