MicroRNAs upregulated during HIV infection target peroxisome biogenesis factors: Implications for virus biology, disease mechanisms and neuropathology.
MicroRNAs upregulated during HIV infection target peroxisome biogenesis factors: Implications for virus biology, disease mechanisms and neuropathology.
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DOI：
10.1371/journal.ppat.1006360
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发表时间：
2017-06
期刊：
影响因子：
6.7
通讯作者：
Hobman TC
中科院分区：
文献类型：
--
作者：
Xu Z;Asahchop EL;Branton WG;Gelman BB;Power C;Hobman TC
HIV 相关神经认知障碍 (HAND) 是一种神经系统综合征，影响高达 25% 的 HIV/AIDS 患者。多种致病机制导致 HAND 症状的发生，包括慢性神经炎症和神经变性。与 HAND 发生相关的因素之一是大脑中宿主细胞 microRNA (miRNA) 表达的改变。在这里，我们检查了患有和不患有 HAND 的 HIV/AIDS 患者的大脑 miRNA 谱。我们的分析揭示了 HAND 患者脑组织中 17 种 miRNA 的差异表达。上调的 miRNA 子集（miR-500a-5p、miR-34c-3p、miR-93-3p 和 miR-381-3p）预计会靶向过氧化物酶体生物发生因子（PEX2、PEX7、PEX11B 和 PEX13）。这些 miRNA 在转染细胞中的表达显着降低了过氧化物酶体蛋白的水平，并随之减少了过氧化物酶体的数量或影响了其形态。 miR-500a-5p、miR-34c-3p、miR-93-3p 和 miR-381-3p 的水平不仅在 HAND 患者大脑中升高，而且在 HIV 感染原代巨噬细胞期间也上调。此外，在 HIV 感染的巨噬细胞以及 HIV 感染患者的脑组织中观察到过氧化物酶体蛋白的同时损失。通过阻断上调 miRNA 的功能，可以消除 HIV 诱导的过氧化物酶体损失。总体而言，这些发现指出了 HIV 患者大脑中以前未被识别的 miRNA 表达模式。通过上调抑制过氧化物酶体生物发生因子的 miRNA 来靶向过氧化物酶体，可能代表了 HIV-1 颠覆先天免疫反应和/或导致神经认知功能障碍的新机制。宿主细胞采用多种抗病毒防御系统，但大多数病毒已经开发出有效的对策。导致终身感染的病毒（例如艾滋病毒）在破坏宿主的抗病毒反应方面特别成功。虽然长期以来人们都知道线粒体是抗病毒信号传导的关键枢纽，但直到最近才发现过氧化物酶体对于这一过程也很重要。过氧化物酶体是小而众多的结构，以其在脂质代谢中的作用而闻名。新证据表明，西尼罗河病毒和登革热病毒等病原病毒通过隔离和降解关键的生物发生因子来阻止过氧化物酶体的产生。在本研究中，我们报告艾滋病毒通过一种全新的机制显着减少受感染细胞中过氧化物酶体的数量。具体来说，感染 HIV 的细胞表达高水平的 microRNA，抑制过氧化物酶体形成所需蛋白质的产生。有趣的是，患有 HIV 相关神经认知障碍的患者大脑中这些 microRNA 的水平升高。因此，除了影响抗病毒信号传导之外，HIV感染期间过氧化物酶体的损失也可能导致神经系统疾病的发生。了解病原病毒如何影响过氧化物酶体生物合成和同源抗病毒信号传导可能最终会带来新的治疗途径和预防长期后遗症。
HIV-associated neurocognitive disorders (HAND) represent a spectrum neurological syndrome that affects up to 25% of patients with HIV/AIDS. Multiple pathogenic mechanisms contribute to the development of HAND symptoms including chronic neuroinflammation and neurodegeneration. Among the factors linked to development of HAND is altered expression of host cell microRNAs (miRNAs) in brain. Here, we examined brain miRNA profiles among HIV/AIDS patients with and without HAND. Our analyses revealed differential expression of 17 miRNAs in brain tissue from HAND patients. A subset of the upregulated miRNAs (miR-500a-5p, miR-34c-3p, miR-93-3p and miR-381-3p), are predicted to target peroxisome biogenesis factors (PEX2, PEX7, PEX11B and PEX13). Expression of these miRNAs in transfected cells significantly decreased levels of peroxisomal proteins and concomitantly decreased peroxisome numbers or affected their morphology. The levels of miR-500a-5p, miR-34c-3p, miR-93-3p and miR-381-3p were not only elevated in the brains of HAND patients, but were also upregulated during HIV infection of primary macrophages. Moreover, concomitant loss of peroxisomal proteins was observed in HIV-infected macrophages as well as in brain tissue from HIV-infected patients. HIV-induced loss of peroxisomes was abrogated by blocking the functions of the upregulated miRNAs. Overall, these findings point to previously unrecognized miRNA expression patterns in the brains of HIV patients. Targeting peroxisomes by up-regulating miRNAs that repress peroxisome biogenesis factors may represent a novel mechanism by which HIV-1 subverts innate immune responses and/or causes neurocognitive dysfunction. Host cells employ a myriad of antiviral defense systems but most viruses have developed effective countermeasures. Viruses such as HIV that cause lifelong infections are particularly successful in subverting the host antiviral response. While mitochondria have long been known to be critical hubs for antiviral signaling, it has only recently become apparent that peroxisomes are also important for this process. Peroxisomes are small and numerous structures that are best known for their roles in lipid metabolism. New evidence suggests that pathogenic viruses such as West Nile and Dengue viruses block the production of peroxisomes by sequestering and degradation a critical biogenesis factor. In the present study, we report that HIV significantly reduces the number of peroxisomes in infected cells via a completely novel mechanism. Specifically, HIV-infected cells express high levels of microRNAs that inhibit production of proteins required for peroxisome formation. Interestingly, levels of these microRNAs were elevated in the brains of patients with HIV-associated neurocognitive disorders. Thus, as well as affecting antiviral signaling, loss of peroxisomes during HIV infection may contribute to development of neurological disorders. Understanding how pathogenic viruses affect peroxisome biogenesis and cognate antiviral signaling may ultimately lead to novel therapeutic avenues and prevention of long-term sequelae.