Cheng Yan, Jung Jaekeun, Guo Liyang, Shuboni-Mulligan Dorela D, Chen Jian-Fu, Hu Wenhui, Guo Ming-Lei
Department of Biomedical and Translational Sciences, Macro & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA 23507, USA.
Center for Craniofacial Molecular Biology, University of Southern California (USC), Los Angeles, CA 90033, USA.
Brain Behav Immun. 2025 Jan;123:108-122. doi: 10.1016/j.bbi.2024.09.011. Epub 2024 Sep 10.
Chronic HIV infection can dysregulate lipid/cholesterol metabolism in the peripheral system, contributing to the higher incidences of diabetes and atherosclerosis in HIV (+) individuals. Recently, accumulating evidence indicate that HIV proteins can also dysregulate lipid/cholesterol metabolism in the brain and such dysregulation could be linked with the pathogenesis of HIV-associated neurological disorders (HAND)/NeuroHIV. To further characterize the association between lipid/cholesterol metabolism and HAND, we employed HIV-inducible transactivator of transcription (iTAT) and control mice to compare their brain lipid profiles. Our results reveal that HIV-iTAT mice possess dysregulated lipid profiles and have increased numbers of lipid droplets (LDs) accumulation microglia (LDAM) in the brains. HIV protein TAT can upregulate LDs formation through enhancing the lipid/cholesterol synthesis in vitro. Mechanistically, HIV-TAT increases the expression of sterol regulatory element-binding protein 2 (SREBP2) through microRNA-124 downregulation. Cholesterol synthesis inhibition can block HIV-TAT-mediated NLRP3 inflammasome activation and microglial activation in vitro as well as mitigate aging-related behavioral impairment and memory deficiency in HIV-iTAT mice. Taken together, our results indicate an inherent role of lipid metabolism and LDAM in the pathogenesis of NeuroHIV (immunometabolism). These findings suggest that LDAM reversal through modulating lipid/cholesterol metabolism could be a novel therapeutic target for ameliorating NeuroHIV symptoms in chronic HIV (+) individuals.
慢性HIV感染可使外周系统的脂质/胆固醇代谢失调，导致HIV阳性个体患糖尿病和动脉粥样硬化的几率更高。最近，越来越多的证据表明，HIV蛋白也会使大脑中的脂质/胆固醇代谢失调，这种失调可能与HIV相关神经障碍（HAND）/神经HIV的发病机制有关。为了进一步阐明脂质/胆固醇代谢与HAND之间的关联，我们使用HIV诱导的转录激活因子（iTAT）小鼠和对照小鼠来比较它们的脑脂质谱。我们的结果显示，HIV-iTAT小鼠的脂质谱失调，大脑中脂质滴（LDs）积累的小胶质细胞（LDAM）数量增加。HIV蛋白TAT可通过增强体外脂质/胆固醇合成来上调LDs的形成。从机制上讲，HIV-TAT通过下调微小RNA-124来增加固醇调节元件结合蛋白2（SREBP2）的表达。胆固醇合成抑制可在体外阻断HIV-TAT介导的NLRP3炎性小体激活和小胶质细胞激活，并减轻HIV-iTAT小鼠与衰老相关的行为障碍和记忆缺陷。综上所述，我们的结果表明脂质代谢和LDAM在神经HIV发病机制（免疫代谢）中具有内在作用。这些发现表明，通过调节脂质/胆固醇代谢来逆转LDAM可能是改善慢性HIV阳性个体神经HIV症状的一种新的治疗靶点。
