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封闭蛋白通过调节干扰素刺激的 OAS 基因家族调节 HIV-1 感染。

Occludin Regulates HIV-1 Infection by Modulation of the Interferon Stimulated OAS Gene Family.

机构信息

Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, 528E Gautier Bldg. 1011 NW 15th Street, Miami, FL, 11336, USA.

出版信息

Mol Neurobiol. 2023 Sep;60(9):4966-4982. doi: 10.1007/s12035-023-03381-0. Epub 2023 May 20.

DOI:10.1007/s12035-023-03381-0
PMID:37209263
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10199280/
Abstract

HIV-1-associated blood brain barrier (BBB) alterations and neurocognitive disorders are frequent clinical manifestations in HIV-1 infected patients. The BBB is formed by cells of the neurovascular unit (NVU) and sealed together by tight junction proteins, such as occludin (ocln). Pericytes are a key cell type of NVU that can harbor HIV-1 infection via a mechanism that is regulated, at least in part, by ocln. After viral infection, the immune system starts the production of interferons, which induce the expression of the 2'-5'-oligoadenylate synthetase (OAS) family of interferon stimulated genes and activate the endoribonuclease RNaseL that provides antiviral protection by viral RNA degradation. The current study evaluated the involvement of the OAS genes in HIV-1 infection of cells of NVU and the role of ocln in controlling OAS antiviral signaling pathway. We identified that ocln modulates the expression levels of the OAS1, OAS2, OAS3, and OASL genes and proteins and, in turn, that the members of the OAS family can influence HIV replication in human brain pericytes. Mechanistically, this effect was regulated via the STAT signaling. HIV-1 infection of pericytes significantly upregulated expression of all OAS genes at the mRNA level but selectively OAS1, OAS2, and OAS3 at the protein level. Interestingly no changes were found in RNaseL after HIV-1 infection. Overall, these results contribute to a better understanding of the molecular mechanisms implicated in the regulation of HIV-1 infection in human brain pericytes and suggest a novel role for ocln in controlling of this process.

摘要

HIV-1 相关的血脑屏障（BBB）改变和神经认知障碍是 HIV-1 感染患者常见的临床表现。BBB 由神经血管单元（NVU）的细胞组成，并通过紧密连接蛋白（如闭合蛋白[ocln]）紧密连接在一起。周细胞是 NVU 的关键细胞类型，可以通过一种至少部分受 ocln 调节的机制感染 HIV-1。病毒感染后，免疫系统开始产生干扰素，干扰素诱导 2'-5'-寡聚腺苷酸合成酶（OAS）家族干扰素刺激基因的表达，并激活内切核糖核酸酶 RNaseL 通过病毒 RNA 降解提供抗病毒保护。本研究评估了 OAS 基因在 HIV-1 感染 NVU 细胞中的作用以及 ocln 在控制 OAS 抗病毒信号通路中的作用。我们发现 ocln 调节 OAS1、OAS2、OAS3 和 OASL 基因和蛋白的表达水平，反过来，OAS 家族成员可以影响人类脑周细胞中的 HIV 复制。从机制上讲，这种效应是通过 STAT 信号调节的。周细胞感染 HIV-1 显著上调所有 OAS 基因的 mRNA 水平，但选择性上调 OAS1、OAS2 和 OAS3 的蛋白水平。有趣的是，HIV-1 感染后 RNaseL 没有变化。总的来说，这些结果有助于更好地理解调节 HIV-1 感染人类脑周细胞的分子机制，并提示 ocln 在控制该过程中具有新的作用。

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