背景:自从联合抗逆转录病毒疗法(cART)引入以来,由于在cART中使用的许多药物进入中枢神经系统(CNS)的渗透性相对较低,因此脑已经成为重要的人类免疫缺陷病毒(HIV)储库。鉴于直接评估HIV感染者(PLWH)大脑中急性HIV感染的固有局限性,动物模型,比如人性化的老鼠模型,提供了最有效的方法来研究不同病毒株的作用及其对CNS中HIV感染的影响。在人源化骨髓/肝脏/胸腺(BLT)小鼠模型中评估HIV-1感染期间的CNS病理学,对五个中枢神经系统区域进行了组织学分析,包括额叶皮层,海马体,纹状体,小脑,和脊髓,描绘神经元(MAP2ab,神经)和神经炎症(GFAP,Iba-1)在感染后2周和8周后由两种病毒株诱导的变化。
结果:研究结果表明,感染HIV的BLT小鼠的大脑中有感染HIV的人类细胞,证明了HIV的神经入侵.Further,两种病毒株,HIV-1JR-CSF和HIV-1CH040在两个时间点感染HIV后,在所有CNS区域诱导神经元损伤和星形胶质增生,如MAP2ab的减少和GFAP荧光信号的增加所证明的,分别。重要的是,与HIV-1CH040感染相比,HIV-1JR-CSF感染对特定CNS区域的神经元健康有更突出的影响,随着NeuN+神经元数量的减少,特别是在额叶皮层。另一方面,感染HIV-1CH040对神经炎症表现出更突出的作用,通过GFAP信号的增加和/或Iba-1+小胶质细胞数量的增加来评估,在CNS地区。
结论:这些发现表明,在急性HIV感染期间,中枢神经系统的病理分布很普遍。然而,中枢神经系统中的神经元损失和神经炎症的程度取决于菌株,表明HIV菌株会引起不同的中枢神经系统病理。
BACKGROUND: Since the introduction of combination antiretroviral therapy (cART) the brain has become an important human immunodeficiency virus (HIV) reservoir due to the relatively low penetration of many drugs utilized in cART into the central nervous system (CNS). Given the inherent limitations of directly assessing acute HIV infection in the brains of people living with HIV (PLWH), animal models, such as humanized mouse models, offer the most effective means of studying the effects of different viral strains and their impact on HIV infection in the CNS. To evaluate CNS pathology during HIV-1 infection in the humanized bone marrow/liver/thymus (BLT) mouse model, a histological analysis was conducted on five CNS regions, including the frontal cortex, hippocampus, striatum, cerebellum, and spinal cord, to delineate the neuronal (MAP2ab, NeuN) and neuroinflammatory (GFAP, Iba-1) changes induced by two viral strains after 2 weeks and 8 weeks post-infection.
RESULTS: Findings reveal HIV-infected human cells in the brain of HIV-infected BLT mice, demonstrating HIV neuroinvasion. Further, both viral strains, HIV-1JR-CSF and HIV-1CH040, induced neuronal injury and astrogliosis across all CNS regions following HIV infection at both time points, as demonstrated by decreases in MAP2ab and increases in GFAP fluorescence signal, respectively. Importantly, infection with HIV-1JR-CSF had more prominent effects on neuronal health in specific CNS regions compared to HIV-1CH040 infection, with decreasing number of NeuN+
neurons, specifically in the frontal cortex. On the other hand, infection with HIV-1CH040 demonstrated more prominent effects on neuroinflammation, assessed by an increase in GFAP signal and/or an increase in number of Iba-1+ microglia, across CNS regions.
CONCLUSIONS: These findings demonstrate that CNS pathology is widespread during acute HIV infection. However, neuronal loss and the magnitude of neuroinflammation in the CNS is strain dependent indicating that strains of HIV cause differential CNS pathologies.