Weiselberg Jessica, Niu Meng, Hernandez Cristian A, Fox Howard S, Calderon Tina M, Berman Joan W
Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA.
Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Int J Mol Sci. 2025 Sep 12;26(18):8875. doi: 10.3390/ijms26188875.
HIV-associated neurocognitive impairment (HIV-NCI), a comorbidity of human immunodeficiency virus (HIV) infection, affects up to 50% of people with HIV (PWH). HIV-infected monocytes that transmigrate across the blood-brain barrier and mature into macrophages establish a central nervous system (CNS) viral reservoir that activates and infects parenchymal cells, contributing to neuronal damage that characterizes HIV-NCI. Methamphetamine (meth) use is prevalent in PWH and further impairs cognitive functioning. To examine whether meth-mediated dysregulation of macrophage functions may contribute to increased HIV-NCI, we characterized differential gene expression in primary human HIV-infected macrophages treated daily with meth for five days by RNA-sequencing. We identified increases in multiple gene isoforms of metallothionein 1 (MT1), a heavy metal binding protein involved in protective mechanisms against metal toxicity and oxidative stress. Nuclear localization of MT1 protein was previously shown to either positively or negatively affect nuclear factor κB (NF-κB) activity in a cell type specific manner, with nuclear MT1 contributing to LPS-induced TNF-α and IL-6 in macrophages. We found that daily meth treatment for one to five days increased nuclear localization of MT1 in macrophages acutely infected with HIV which was associated with increased LPS-induced CXCL8 and CCL8, and a trend towards increased basal and/or LPS-induced expression of other cytokines/chemokines, including TNF-α and IL-6, that was donor specific. Reactive oxygen species (ROS) levels were not changed with meth treatment although there was a donor specific trend towards increased ROS with multiple days of meth treatment. These data indicate that repeated exposure of macrophages to meth in the context of HIV increases nuclear MT1 localization, which is associated with increased inflammatory mediator production, and therefore may be a mechanism that contributes to meth-mediated exacerbation of HIV-NCI.
人类免疫缺陷病毒（HIV）相关神经认知障碍（HIV-NCI）是HIV感染的一种合并症，影响着多达50%的HIV感染者（PWH）。穿越血脑屏障并成熟为巨噬细胞的HIV感染单核细胞建立了一个中枢神经系统（CNS）病毒储存库，该储存库激活并感染实质细胞，导致HIV-NCI所特有的神经元损伤。甲基苯丙胺（冰毒）的使用在PWH中很普遍，并且会进一步损害认知功能。为了研究冰毒介导的巨噬细胞功能失调是否可能导致HIV-NCI加重，我们通过RNA测序对每天用冰毒处理五天的原代人类HIV感染巨噬细胞中的差异基因表达进行了表征。我们发现金属硫蛋白1（MT1）的多种基因亚型增加，MT1是一种重金属结合蛋白，参与针对金属毒性和氧化应激的保护机制。先前研究表明，MT1蛋白的核定位以细胞类型特异性方式对核因子κB（NF-κB）活性产生正向或负向影响，核MT1有助于巨噬细胞中脂多糖（LPS）诱导的肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）的产生。我们发现，对急性感染HIV的巨噬细胞进行一到五天的每日冰毒处理会增加MT1的核定位，这与LPS诱导的趋化因子CXCL8和CCL8增加相关，并且其他细胞因子/趋化因子（包括TNF-α和IL-6）的基础表达和/或LPS诱导表达有增加的趋势，这具有供体特异性。尽管多次进行冰毒处理后有供体特异性的活性氧（ROS）增加趋势，但冰毒处理并未改变ROS水平。这些数据表明，在HIV感染的情况下，巨噬细胞反复接触冰毒会增加MT1的核定位，这与炎症介质产生增加相关，因此可能是导致冰毒介导的HIV-NCI加重的一种机制。
