Department of Medical Microbiology and Immunology, University of California, Davis, California, USA.
J Virol. 2014 Jun;88(11):6268-80. doi: 10.1128/JVI.00097-14. Epub 2014 Mar 26.
Epithelial barrier dysfunction during human immunodeficiency virus (HIV) infection has largely been attributed to the rapid and severe depletion of CD4(+) T cells in the gastrointestinal (GI) tract. Although it is known that changes in mucosal gene expression contribute to intestinal enteropathy, the role of small noncoding RNAs, specifically microRNA (miRNA), has not been investigated. Using the simian immunodeficiency virus (SIV)-infected nonhuman primate model of HIV pathogenesis, we investigated the effect of viral infection on miRNA expression in intestinal mucosa. SIV infection led to a striking decrease in the expression of mucosal miRNA compared to that in uninfected controls. This decrease coincided with an increase in 5'-3'-exoribonuclease 2 protein and alterations in DICER1 and Argonaute 2 expression. Targets of depleted miRNA belonged to molecular pathways involved in epithelial proliferation, differentiation, and immune response. Decreased expression of several miRNA involved in maintaining epithelial homeostasis in the gut was localized to the proliferative crypt region of the intestinal epithelium. Our findings suggest that SIV-induced decreased expression of miRNA involved in epithelial homeostasis, disrupted expression of miRNA biogenesis machinery, and increased expression of XRN2 are involved in the development of epithelial barrier dysfunction and gastroenteropathy.
MicroRNA (miRNA) regulate the development and function of intestinal epithelial cells, and many viruses disrupt normal host miRNA expression. In this study, we demonstrate that SIV and HIV disrupt expression of miRNA in the small intestine during infection. The depletion of several key miRNA is localized to the proliferative crypt region of the gut epithelium. These miRNA are known to control expression of genes involved in inflammation, cell death, and epithelial maturation. Our data indicate that this disruption might be caused by altered expression of miRNA biogenesis machinery during infection. These findings suggest that the disruption of miRNA in the small intestine likely plays a role in intestinal enteropathy during HIV infection.
在人类免疫缺陷病毒（HIV）感染期间，上皮屏障功能障碍主要归因于胃肠道（GI）中 CD4(+)T 细胞的快速和严重耗竭。尽管已知粘膜基因表达的变化导致肠病，但小非编码 RNA，特别是 microRNA（miRNA）的作用尚未得到研究。我们使用猴免疫缺陷病毒（SIV）感染的 HIV 发病机制非人类灵长类动物模型，研究了病毒感染对肠道粘膜中 miRNA 表达的影响。与未感染对照相比，SIV 感染导致粘膜 miRNA 的表达明显下降。这种减少与 5'-3'-外切核酸酶 2 蛋白的增加以及 DICER1 和 Argonaute 2 表达的改变同时发生。耗尽的 miRNA 的靶标属于涉及上皮增殖、分化和免疫反应的分子途径。肠道上皮细胞稳态维持所涉及的几种 miRNA 的表达减少，定位于肠上皮的增殖隐窝区。我们的研究结果表明，SIV 诱导的与上皮稳态有关的 miRNA 表达减少、miRNA 生物发生机制表达受损以及 XRN2 表达增加与上皮屏障功能障碍和胃肠道疾病的发展有关。
miRNA（miRNA）调节肠道上皮细胞的发育和功能，许多病毒会破坏正常的宿主 miRNA 表达。在这项研究中，我们证明 SIV 和 HIV 在感染期间破坏小肠中 miRNA 的表达。几种关键 miRNA 的耗竭定位于肠道上皮的增殖隐窝区。这些 miRNA 已知可控制参与炎症、细胞死亡和上皮成熟的基因表达。我们的数据表明，这种耗竭可能是由于感染期间 miRNA 生物发生机制的表达改变引起的。这些发现表明，小干扰 RNA 在小肠中的破坏可能在 HIV 感染期间的肠道肠病中发挥作用。
