Comparative Medicine Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
National Toxicology Program Laboratory, National Institute of Environmental Health Sciences (NIEHS), P.O. Box 12233, MD E1-07, Research Triangle Park, NC, 27709, USA.
Neurotox Res. 2019 Oct;36(3):563-582. doi: 10.1007/s12640-019-00077-z. Epub 2019 Jul 8.
Animal models have been used to study cellular processes related to human immunodeficiency virus-1 (HIV-1)-associated neurocognitive disorders (HAND). The HIV-1 transgenic (Tg) rat expresses HIV viral genes except the gag-pol replication genes and exhibits neuropathological features similar to HIV patients receiving combined antiretroviral therapy (cART). Using this rat, alterations in dopaminergic function have been demonstrated; however, the data for neuroinflammation and glial reactivity is conflicting. Differences in behavior, tyrosine hydroxylase (TH) immunoreactivity, neuroinflammation, and glia reactivity were assessed in HIV-1 Tg male rats. At 6 and 12 weeks of age, rotarod performance was diminished, motor activity was not altered, and active avoidance latency performance and memory were diminished in HIV-1 Tg rats. TH immunoreactivity in the substantia nigra (SN) was decreased at 8 months but not at 2-5 months. At 5 months, astrocyte and microglia morphology was not altered in the cortex, hippocampus, or SN. In the striatum, astrocytes were unaltered, microglia displayed slightly thickened proximal processes, mRNA levels for Iba1 and Cd11b were elevated, and interleukin (Il)1α,Cxcr3, and cell adhesion molecule, Icam, decreased. In the hippocampus, mRNA levels for Tnfa and Cd11b were slightly elevated. No changes were observed in the cortex or SN. The data support an age-related effect of HIV proteins upon the nigrostriatal dopaminergic system and suggest an early response of microglia in the terminal synaptic region with little evidence of an associated neuroinflammatory response across brain regions.
动物模型已被用于研究与人类免疫缺陷病毒 1（HIV-1）相关的神经认知障碍（HAND）相关的细胞过程。HIV-1 转基因（Tg）大鼠表达 HIV 病毒基因，但不表达 gag-pol 复制基因，并表现出与接受联合抗逆转录病毒治疗（cART）的 HIV 患者相似的神经病理学特征。使用这种大鼠，已经证明多巴胺能功能发生了改变；然而，神经炎症和神经胶质反应的数据存在矛盾。在 HIV-1 Tg 雄性大鼠中评估了行为、酪氨酸羟化酶（TH）免疫反应性、神经炎症和神经胶质反应的差异。在 6 和 12 周龄时，HIV-1 Tg 大鼠的旋转棒表现能力下降，运动活动未改变，主动回避潜伏期表现和记忆能力下降。8 个月时，SN 中的 TH 免疫反应性降低，但 2-5 个月时没有降低。在 5 个月时，皮质、海马体或 SN 中的星形胶质细胞和小胶质细胞形态没有改变。在纹状体中，星形胶质细胞没有改变，小胶质细胞的近端突起稍厚，Iba1 和 Cd11b 的 mRNA 水平升高，白细胞介素（Il）1α、Cxcr3 和细胞间黏附分子（Icam）减少。在海马体中，Tnfa 和 Cd11b 的 mRNA 水平略有升高。在皮质或 SN 中未观察到变化。该数据支持 HIV 蛋白对黑质纹状体多巴胺能系统的年龄相关影响，并提示微胶质细胞在终末突触区域的早期反应，而整个脑区的神经炎症反应证据很少。
