Crist Richard C, Chehimi Samar N, Divakaran Saurabh S, Montague Michael J, Tremblay Sébastien, Snyder-Mackler Noah, Bohlen Martin O, Chiou Kenneth L, Zintel Trish M, Platt Michael L, Juul Halvor, Silvestri Guido, Hayes Matthew R, Kolson Dennis L, Reiner Benjamin C
Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Transl Psychiatry. 2025 Jan 31;15(1):38. doi: 10.1038/s41398-025-03261-2.
Understanding the neurobiological mechanisms underlying HIV-associated neurocognitive decline in people living with HIV is frequently complicated by an inability to analyze changes across the course of the infection and frequent presence of comorbid psychiatric and substance use disorders. Preclinical non-human primate simian immunodeficiency virus (SIV) models help address these shortcomings. However, SIV studies frequently target protracted endpoints, limiting our understanding of the neuromolecular alterations during the early post-infection window. To begin to address this knowledge gap, we utilized single nuclei transcriptomics to examine frontal cortex samples of rhesus macaques 10- and 20-days post-SIV infection, compared to non-infected controls. We identify and validated a decrease in inhibitory neurons during the early post infection window, representing a potential substrate of longer-term injury and neurocognitive impairment in people living with HIV. Differential expression identified alterations in cellular subtype gene expression that persisted over the 20-day time course and short-lived differences only detected at 10-days post-SIV infection. In silico predicted regulatory mechanisms and dysregulated neural signaling pathways are presented. Analysis of cell-cell interaction networks identify altered signal pathways in the frontal cortex that may represent regional alterations in cell-cell communications. In total, these results identify cell type-specific molecular mechanisms putatively capable of underlying long-term neurocognitive alterations in persons living with HIV.
了解HIV感染者中与HIV相关的神经认知功能下降的神经生物学机制常常因无法分析感染过程中的变化以及频繁出现的合并精神疾病和物质使用障碍而变得复杂。临床前的非人灵长类动物猴免疫缺陷病毒（SIV）模型有助于解决这些缺点。然而，SIV研究通常针对长期终点，限制了我们对感染后早期窗口期神经分子改变的理解。为了开始填补这一知识空白，我们利用单核转录组学来检查SIV感染后10天和20天的恒河猴额叶皮质样本，并与未感染的对照组进行比较。我们识别并验证了感染后早期窗口期抑制性神经元的减少，这代表了HIV感染者长期损伤和神经认知障碍的潜在基础。差异表达确定了细胞亚型基因表达的改变，这些改变在20天的时间进程中持续存在，而短暂的差异仅在SIV感染后10天检测到。本文还展示了计算机预测的调控机制和失调的神经信号通路。对细胞间相互作用网络的分析确定了额叶皮质中改变的信号通路，这些通路可能代表细胞间通讯的区域改变。总的来说，这些结果确定了可能是HIV感染者长期神经认知改变基础的细胞类型特异性分子机制。
