Viral protein R of HIV type-1 induces retrotransposition and upregulates glutamate synthesis by the signal transducer and activator of transcription 1 signaling pathway
Viral protein R of HIV type-1 induces retrotransposition and upregulates glutamate synthesis by the signal transducer and activator of transcription 1 signaling pathway
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DOI：
10.1111/1348-0421.12266
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发表时间：
2015-07-01
影响因子：
2.6
通讯作者：
Ishizaka, Yukihito
中科院分区：
文献类型：
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作者：
Doi, Akihiro;Iijima, Kenta;Ishizaka, Yukihito
HIV-1的病毒蛋白R （Vpr）在巨噬细胞内的病毒复制中起重要作用。各种证据表明巨噬细胞中Vpr的表达引起免疫发病；然而，潜在的机制尚未完全了解。本研究表明，重组Vpr （rVpr）在巨噬细胞样细胞系RAW264.7中诱导长散布元件-1的反转录转位，并激活逆转录酶依赖的免疫毒性级联反应，包括IFN-的产生和信号换能器和转录激活因子1 （STAT1）的磷酸化。基于CRISPR/Cas9 nickase系统的基因敲除实验进一步证实，环鸟苷单磷酸腺苷单磷酸合成酶（cGAS）和干扰素基因刺激因子（STING）分别负责IFN-的产生和STAT1的磷酸化。此外，rVpr被发现增加谷氨酰胺酶C的产生，谷氨酰胺酶C是谷氨酸合成的调节因子，也依赖于cGAS-STING途径。结合谷氨酰胺酶C参与hiv相关神经认知障碍（HAND）发病机制的报道，以及在hiv -1阳性患者的脑脊液中检测到Vpr，本文讨论了Vpr诱导的L1-RTP和免疫毒性级联反应在HAND发展中的可能作用。
Viral protein R (Vpr) of HIV-1 plays an important role in viral replication in macrophages. Various lines of evidence suggest that expression of Vpr in macrophages causes immunopathogenesis; however, the underlying mechanism is not yet fully understood. In this study, it was shown that recombinant Vpr (rVpr) induces retrotransposition of long interspersed element-1 in RAW264.7, a macrophage-like cell line, and activates reverse transcriptase-dependent immunotoxic cascades including production of IFN- and phosphorylation of signal transducer and activator of transcription 1 (STAT1). Knockout experiments based on the CRISPR/Cas9 nickase system further demonstrated that cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and stimulator of interferon gene (STING) are responsible for IFN- production and STAT1 phosphorylation, respectively. Moreover, rVpr was found to increase production of glutaminase C, a regulator of glutamate synthesis, which is also dependent on the cGAS-STING pathway. Taken together with reports that glutaminase C is involved in the pathogenesis of HIV-associated neurocognitive disorder (HAND) and that Vpr is detectable in the cerebrospinal fluid of HIV-1-positive patients, a possible role of Vpr-induced L1-RTP and immunotoxic cascades in the development of HAND is discussed.