人类免疫缺陷病毒(HIV)因其对免疫系统的深远影响而被广泛认可。尽管HIV主要影响外周CD4T细胞,其对中枢神经系统(CNS)的影响不容忽视。在大脑中,小胶质细胞和中枢神经系统相关巨噬细胞(CAM)作为艾滋病毒的主要目标,以及非人灵长类动物中的猿猴免疫缺陷病毒(SIV)。这种感染可导致神经效应和病毒库的建立。鉴于我们对这些细胞在体内如何应对急性中枢神经系统感染的理解存在差距,我们在SIV感染后12天,对三只恒河猴的大脑中的骨髓细胞进行了单细胞RNA测序(scRNA-seq),还有三个未感染的对照.我们的分析揭示了六个不同的小胶质细胞簇,包括稳态小胶质细胞,预激活的小胶质细胞,和活化的小胶质细胞表达高水平的炎症和疾病相关分子。为了应对急性SIV感染,稳态和预激活小胶质细胞的数量减少,而活化和疾病相关的小胶质细胞增加。所有小胶质细胞簇都显示出MHCI类分子和干扰素相关基因的上调,表明它们在急性期防御SIV的关键作用。所有小胶质细胞簇也上调与细胞衰老相关的基因。此外,我们确定了两个不同的CAM群体:CD14低CD16hi和CD14高CD16低CAM。有趣的是,在急性SIV感染期间,主要的CAM群体变为具有炎症表型的群体。值得注意的是,一个小胶质细胞和一个巨噬细胞群内的特定上调基因与神经退行性通路相关,提示与神经认知障碍的潜在联系。这项研究揭示了病毒感染之间复杂的相互作用,先天免疫反应,和中枢神经系统,为未来的调查提供有价值的见解。
■HIV进入中枢神经系统(CNS)会导致神经功能障碍,包括HIV相关神经认知障碍(HAND),并建立了病毒库。虽然小胶质细胞和CNS相关巨噬细胞(CAM)是CNS中HIV的主要靶标,他们在急性HIV感染期间的反应仍然不明确.为了解决这个问题,我们使用scRNA-seq技术研究了在急性SIV感染期间恒河猴的小胶质细胞和CAM群体。通过识别与不同表型相关的签名基因并将其定位到各种生物学和病理学途径,我们发现了两个与神经退行性疾病密切相关的骨髓细胞簇。此外,其他集群与炎症途径相关,提示大脑中不同骨髓细胞群之间不同程度的激活,可能由不同的信号通路介导。所有小胶质细胞簇都出现了细胞衰老途径的迹象。这些发现揭示了急性SIV感染时脑中不同髓系表型的免疫和病理效应,为针对这一关键阶段并旨在消除病毒库的未来治疗策略提供有价值的见解。
Human Immunodeficiency Virus (HIV) is widely acknowledged for its profound impact on the immune system. Although HIV primarily affects peripheral CD4 T cells, its influence on the central nervous system (CNS) cannot be overlooked. Within the brain, microglia and CNS-associated macrophages (CAMs) serve as the primary targets for HIV, as well as for the simian immunodeficiency virus (
SIV) in nonhuman primates. This infection can lead to neurological effects and the establishment of a viral reservoir. Given the gaps in our understanding of how these cells respond in vivo to acute CNS infection, we conducted single-cell RNA sequencing (scRNA-seq) on myeloid cells from the brains of three rhesus macaques 12-days after
SIV infection, along with three uninfected controls. Our analysis revealed six distinct microglial clusters including homeostatic microglia, preactivated microglia, and activated microglia expressing high levels of inflammatory and disease-related molecules. In response to acute
SIV infection, the population of homeostatic and preactivated microglia decreased, while the activated and disease-related microglia increased. All microglial clusters exhibited upregulation of MHC class I molecules and interferon-related genes, indicating their crucial roles in defending against
SIV during the acute phase. All microglia clusters also upregulated genes linked to cellular senescence. Additionally, we identified two distinct CAM populations: CD14lowCD16hi and CD14hiCD16low CAMs. Interestingly, during acute
SIV infection, the dominant CAM population changed to one with an inflammatory phenotype. Notably, specific upregulated genes within one microglia and one macrophage cluster were associated with neurodegenerative pathways, suggesting potential links to neurocognitive disorders. This research sheds light on the intricate interactions between viral infection, innate immune responses, and the CNS, providing valuable insights for future investigations.