Borsa Mariana, Ferreira Pedro L C, Petry Andrea, Ferreira Luiz G E, Camargo Maristela M, Bou-Habib Dumith Chequer, Pinto Aguinaldo R
Laboratório de Imunologia Aplicada, Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
Laboratório de Pesquisas sobre o Timo, Instituto Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
Virol J. 2015 May 15;12:77. doi: 10.1186/s12985-015-0298-0.
The unfolded protein response (UPR) is one of the pathways triggered to ensure quality control of the proteins assembled in the endoplasmic reticulum (ER) when cell homeostasis is compromised. This mechanism is primarily composed of three transmembrane proteins serving as stress sensors: PKR-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1). These three proteins' synergic action elicits translation and transcriptional downstream pathways, leading to less protein production and activating genes that encode important proteins in folding processes, including chaperones. Previous reports showed that viruses have evolved mechanisms to curtail or customize this UPR signaling for their own benefit. However, HIV infection's effect on the UPR has scarcely been investigated.
This work investigated UPR modulation by HIV infection by assessing UPR-related protein expression under in vitro and in vivo conditions via Western blotting. Antiretroviral (ARV) drugs' influence on this stress response was also considered.
In in vitro and in vivo analyses, our results confirm that HIV infection activates stress-response components and that ARV therapy contributes to changes in the UPR's activation profile.
This is the first report showing UPR-related protein expression in HIV target cells derived directly from HIV-infected patients receiving different ARV therapies. Thus, two mechanisms may occur simultaneously: interference by HIV itself and the ARV drugs' pharmacological effects as UPR activators. New evidence of how HIV modulates the UPR to enhance its own replication and secure infection success is also presented.
未折叠蛋白反应（UPR）是细胞稳态受到破坏时触发的确保内质网（ER）中组装蛋白质量控制的途径之一。该机制主要由三种作为应激传感器的跨膜蛋白组成：蛋白激酶R样内质网激酶（PERK）、活化转录因子6（ATF6）和肌醇需求酶1（IRE1）。这三种蛋白的协同作用引发翻译和转录下游途径，导致蛋白质产生减少，并激活在折叠过程中编码重要蛋白（包括伴侣蛋白）的基因。先前的报道表明，病毒已经进化出机制来为自身利益而减少或定制这种UPR信号。然而，几乎没有研究过HIV感染对UPR的影响。
本研究通过蛋白质印迹法评估体外和体内条件下与UPR相关的蛋白表达，来研究HIV感染对UPR的调节作用。还考虑了抗逆转录病毒（ARV）药物对这种应激反应的影响。
在体外和体内分析中，我们的结果证实HIV感染会激活应激反应成分，并且ARV疗法会导致UPR激活谱的变化。
这是第一份显示直接来自接受不同ARV疗法的HIV感染患者的HIV靶细胞中与UPR相关蛋白表达的报告。因此，可能同时发生两种机制：HIV本身的干扰以及ARV药物作为UPR激活剂的药理作用。还提供了关于HIV如何调节UPR以增强其自身复制并确保感染成功的新证据。
