Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
Department of Neurosurgery, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
Cells. 2024 Jun 29;13(13):1127. doi: 10.3390/cells13131127.
HIV-associated neurocognitive disorders (HAND) persist under antiretroviral therapy as a complex pathology that has been difficult to study in cellular and animal models. Therefore, we generated an ex vivo human brain slice model of HIV-1 infection from surgically resected adult brain tissue. Brain slice cultures processed for flow cytometry showed >90% viability of dissociated cells within the first three weeks in vitro, with parallel detection of astrocyte, myeloid, and neuronal populations. Neurons within brain slices showed stable dendritic spine density and mature spine morphologies in the first weeks in culture, and they generated detectable activity in multi-electrode arrays. We infected cultured brain slices using patient-matched CD4+ T-cells or monocyte-derived macrophages (MDMs) that were exposed to a GFP-expressing R5-tropic HIV-1 in vitro. Infected slice cultures expressed viral RNA and developed a spreading infection up to 9 days post-infection, which were significantly decreased by antiretrovirals. We also detected infected myeloid cells and astrocytes within slices and observed minimal effect on cellular viability over time. Overall, this human-centered model offers a promising resource to study the cellular mechanisms contributing to HAND (including antiretroviral toxicity, substance use, and aging), infection of resident brain cells, and new neuroprotective therapeutics.
HIV 相关神经认知障碍（HAND）在抗逆转录病毒治疗下仍然存在，是一种复杂的病理学，在细胞和动物模型中很难研究。因此，我们从手术切除的成人脑组织中生成了 HIV-1 感染的离体人脑切片模型。用于流式细胞术的脑切片培养物在体外的前 3 周内显示出 >90%的分离细胞活力，同时平行检测星形胶质细胞、髓样细胞和神经元群体。脑切片中的神经元在培养的前几周内表现出稳定的树突棘密度和成熟的棘突形态，并且它们在多电极阵列中产生可检测的活性。我们使用与患者匹配的 CD4+ T 细胞或单核细胞衍生的巨噬细胞（MDM）感染离体脑切片，这些细胞在体外暴露于 GFP 表达的 R5 嗜性 HIV-1。感染的切片培养物表达病毒 RNA，并在感染后 9 天内发展为扩散感染，抗逆转录病毒药物显著降低了这种感染。我们还在切片中检测到感染的髓样细胞和星形胶质细胞，并且随着时间的推移，细胞活力的影响最小。总的来说，这种以人类为中心的模型为研究导致 HAND 的细胞机制（包括抗逆转录病毒毒性、物质使用和衰老）、驻留脑细胞感染以及新的神经保护治疗方法提供了一个有前途的资源。
