People living with HIV (PLWH) continue to develop HIV-associated neurocognitive disorders despite combination anti-retroviral therapy. Lipocalin-2 (LCN2) is an acute phase protein that has been implicated in neurodegeneration and is upregulated in a transgenic mouse model of HIV-associated brain injury. Here we show that LCN2 is significantly upregulated in neocortex of a subset of HIV-infected individuals with brain pathology and correlates with viral load in CSF and pro-viral DNA in neocortex. However, the question if LCN2 contributes to HIV-associated neurotoxicity or is part of a protective host response required further investigation. We found that the knockout of LCN2 in transgenic mice expressing HIVgp120 in the brain (HIVgp120tg) abrogates behavioral impairment, ameliorates neuronal damage, and reduces microglial activation in association with an increase of the neuroprotective CCR5 ligand CCL4. In vitro experiments show that LCN2 neurotoxicity also depends on microglia and p38 MAPK activity. Genetic ablation of CCR5 in LCN2-deficient HIVgp120tg mice restores neuropathology, suggesting that LCN2 overrides neuroprotection mediated by CCR5 and its chemokine ligands. RNA expression of 168 genes involved in neurotransmission reveals that neuronal injury and protection are each associated with genotype- and sex-specific patterns affecting common neural gene networks. In conclusion, our study identifies LCN2 as a novel factor in HIV-associated brain injury involving CCR5, p38 MAPK and microglia. Furthermore, the mechanistic interaction between LCN2 and CCR5 may serve as a diagnostic and therapeutic target in HIV patients at risk of developing brain pathology and neurocognitive impairment.

中文翻译：

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Lipocalin-2 通过压倒 CCR5 依赖性保护来介导 HIV-1 诱导的神经元损伤和行为缺陷

尽管联合抗逆转录病毒治疗，艾滋病毒感染者 (PLWH) 仍继续发展为艾滋病毒相关的神经认知障碍。Lipocalin-2 (LCN2) 是一种急性期蛋白，它与神经变性有关，在 HIV 相关脑损伤的转基因小鼠模型中上调。在这里，我们显示 LCN2 在 HIV 感染的大脑病理亚组的新皮质中显着上调，并且与 CSF 中的病毒载量和新皮质中的前病毒 DNA 相关。然而，LCN2 是否有助于 HIV 相关的神经毒性或是否是保护性宿主反应的一部分的问题需要进一步调查。我们发现在大脑中表达 HIVgp120 (HIVgp120tg) 的转基因小鼠中敲除 LCN2 可以消除行为障碍，改善神经元损伤，并减少与神经保护性 CCR5 配体 CCL4 增加相关的小胶质细胞活化。体外实验表明 LCN2 神经毒性还取决于小胶质细胞和 p38 MAPK 活性。LCN2 缺陷型 HIVgp120tg 小鼠中 CCR5 的基因消融可恢复神经病理学，这表明 LCN2 超越了由 CCR5 及其趋化因子配体介导的神经保护作用。参与神经传递的 168 个基因的 RNA 表达表明，神经元损伤和保护都与影响常见神经基因网络的基因型和性别特异性模式有关。总之，我们的研究将 LCN2 确定为涉及 CCR5、p38 MAPK 和小胶质细胞的 HIV 相关脑损伤的新因子。此外，