Huang Chang, Qu Qing Rui, Bendayan Reina
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
FASEB J. 2025 Jun 30;39(12):e70751. doi: 10.1096/fj.202500568RR.
Despite the effectiveness and tolerability of antiretroviral therapy (ART) in treating HIV infection, integrase strand transfer inhibitors, particularly dolutegravir (DTG)-based ART, have been associated with various brain complications. Our research group has previously reported that DTG disrupts the blood-brain barrier (BBB) by inducing endoplasmic reticulum (ER) stress. To further understand DTG-associated toxicity, this follow-up study assessed autophagy dysfunction, a critical process that is closely linked to ER stress, using primary cultures of mouse brain microvascular endothelial cells as a robust BBB rodent model. We demonstrated that DTG exposure at therapeutically relevant concentrations significantly increased Sqstm/p62, LC3B-I and LC3B-II protein expression, and downregulated autophagy-related genes Ulk1 and Atg14, suggesting an autophagy inhibition as a result of DTG treatment. This study provides new insights into the toxicological mechanisms of DTG and pathogenesis of DTG-associated brain complications.
尽管抗逆转录病毒疗法（ART）在治疗HIV感染方面具有有效性和耐受性，但整合酶链转移抑制剂，尤其是基于多替拉韦（DTG）的ART，已与各种脑部并发症相关联。我们的研究小组此前曾报道，DTG通过诱导内质网（ER）应激破坏血脑屏障（BBB）。为了进一步了解DTG相关的毒性，这项后续研究使用小鼠脑微血管内皮细胞的原代培养作为强大的BBB啮齿动物模型，评估了自噬功能障碍，这是一个与ER应激密切相关的关键过程。我们证明，在治疗相关浓度下暴露于DTG会显著增加Sqstm/p62、LC3B-I和LC3B-II蛋白表达，并下调自噬相关基因Ulk1和Atg14，表明DTG治疗导致自噬抑制。这项研究为DTG的毒理学机制和DTG相关脑部并发症的发病机制提供了新的见解。
