Torices Silvia, Teglas Timea, Naranjo Oandy, Fattakhov Nikolai, Frydlova Kristyna, Cabrera Rosalba, Osborne Olivia M, Sun Enze, Kluttz Allan, Toborek Michal
University of Miami Miller School of Medicine: University of Miami School of Medicine.
University of Miami School of Medicine.
Res Sq. 2023 Jan 30:rs.3.rs-2501091. doi: 10.21203/rs.3.rs-2501091/v1.
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 (TJ) 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.
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。血脑屏障由神经血管单元（NVU）的细胞形成，并通过紧密连接（TJ）蛋白，如闭合蛋白（ocln）密封在一起。周细胞是神经血管单元的一种关键细胞类型，它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，干扰素诱导干扰素刺激基因的2'-5'-寡腺苷酸合成酶（OAS）家族表达，并激活核糖核酸内切酶RNaseL，RNaseL通过降解病毒RNA提供抗病毒保护。本研究评估了OAS基因在神经血管单元细胞的HIV-1感染中的作用以及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基因及蛋白的表达水平，反过来，OAS家族成员可以影响人脑海绵状细胞中的HIV复制。从机制上讲，这种效应是通过STAT信号传导调节的。周细胞的HIV-1感染在mRNA水平上显著上调了所有OAS基因的表达，但在蛋白水平上选择性上调了OAS1、OAS2和OAS3。有趣的是，HIV-1感染后未发现RNaseL有变化。总体而言，这些结果有助于更好地理解人脑海绵状细胞中HIV-1感染调控所涉及的分子机制，并提示ocln在控制这一过程中具有新的作用。
