PDF(Pubmed)
Abstract：
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.
摘要：
HIV相关的神经认知障碍（HAND）作为一种复杂的病理在抗逆转录病毒治疗下持续存在，难以在细胞和动物模型中进行研究。因此,我们从手术切除的成人脑组织中建立了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显示，在体外的前三周内，解离细胞的存活率>90％，平行检测星形胶质细胞，髓样，和神经元群体。在培养的最初几周，脑片内的神经元显示出稳定的树突脊柱密度和成熟的脊柱形态，它们在多电极阵列中产生可检测的活性。我们使用患者匹配的CD4T细胞或单核细胞衍生的巨噬细胞（MDMs）感染培养的脑切片，这些细胞在体外暴露于表达GFP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天发展为传播感染，抗逆转录病毒药物显着减少。我们还检测到切片中感染的骨髓细胞和星形胶质细胞，并观察到随时间对细胞活力的最小影响。总的来说,这种以人为中心的模型提供了一个有前途的资源来研究导致HAND的细胞机制（包括抗逆转录病毒毒性，物质使用,和老化)，常驻脑细胞的感染，和新的神经保护疗法。
