Li Hailong, McLaurin Kristen A, Mactutus Charles F, Booze Rosemarie M
bioRxiv. 2023 Jan 21:2023.01.20.524942. doi: 10.1101/2023.01.20.524942.
Microglia, which are productively infected by HIV-1, are critical for brain development and maturation, as well as synaptic plasticity. The pathophysiology of HIV-infected microglia and their role in the pathogenesis of HIV-1-associated neurocognitive and affective alterations, however, remains understudied. Three complementary aims were undertaken to critically address this knowledge gap. First, the predominant cell type expressing HIV-1 mRNA in the dorsolateral prefrontal cortex of postmortem HIV-1 seropositive individuals with HAND was investigated. Utilization of a combined RNAscope multiplex fluorescent and immunostaining assay revealed prominent HIV-1 mRNA in microglia of postmortem HIV-1 seropositive individuals with HAND. Second, measures of microglia proliferation and neuronal damage were evaluated in chimeric HIV (EcoHIV) rats. Eight weeks after EcoHIV innoculation, enhanced microglial proliferation was observed in the medial prefrontal cortex (mPFC) of EcoHIV rats, evidenced by an increased number of cells co-localized with both Iba1+ and Ki67+ relative to control animals. Neuronal damage in EcoHIV infected rats was evidenced by pronounced decreases in both synaptophysin and post synaptic density protein 95 (PSD-95), markers of pre-synaptic and post-synaptic damage, respectively. Third, regression analyses were conducted to evaluate whether microglia proliferation mechanistically underlies neuronal damage in EcoHIV and control animals. Indeed, microglia proliferation accounts for 42-68.6% of the variance in synaptic dysfunction. Collectively, microglia proliferation induced by chronic HIV-1 viral protein exposure may underlie the profound synaptodendritic alterations in HIV-1. Understanding how microglia are involved in the pathogenesis of HAND and HIV-1-associated affective disorders affords a key target for the development of novel therapeutics.
小胶质细胞可被HIV-1有效感染，对大脑发育、成熟以及突触可塑性至关重要。然而，HIV感染的小胶质细胞的病理生理学及其在HIV-1相关神经认知和情感改变发病机制中的作用仍未得到充分研究。本研究通过三个互补的目标来严格填补这一知识空白。首先，研究了患有HAND的HIV-1血清阳性个体死后背外侧前额叶皮质中表达HIV-1 mRNA的主要细胞类型。使用RNAscope多重荧光和免疫染色联合检测方法，发现在患有HAND的HIV-1血清阳性个体的小胶质细胞中存在显著的HIV-1 mRNA。其次，在嵌合HIV（EcoHIV）大鼠中评估了小胶质细胞增殖和神经元损伤的指标。EcoHIV接种八周后，在EcoHIV大鼠的内侧前额叶皮质（mPFC）中观察到小胶质细胞增殖增强，与对照动物相比，Iba1+和Ki67+双阳性细胞数量增加证明了这一点。EcoHIV感染大鼠的神经元损伤表现为突触素和突触后密度蛋白95（PSD-95）明显减少，这两种蛋白分别是突触前和突触后损伤的标志物。第三，进行回归分析以评估小胶质细胞增殖是否在机制上是EcoHIV和对照动物神经元损伤的基础。事实上，小胶质细胞增殖占突触功能障碍变异的42%-68.6%。总体而言，慢性HIV-1病毒蛋白暴露诱导的小胶质细胞增殖可能是HIV-1中深刻的突触树突改变的基础。了解小胶质细胞如何参与HAND和HIV-1相关情感障碍的发病机制为开发新型治疗方法提供了一个关键靶点。
