HIV affects 37 million people worldwide, 25–69% of which develop HIV-associated neurocognitive disorders (HAND) regardless of antiviral treatment. HIV infection of the brain decreases cognitive function, disrupts/impairs learning and memory, and reduces quality of life for those affected. HIV-induced neuroinflammation has been associated with viral proteins such as gp120 and Tat, which remain elevated in the CNS even in patients with low peripheral viremia counts. In this study, we examined the effects of gp120 on neuroinflammation in immunodeficient vs. immunocompetent states by examining neuroinflammatory markers in gp120tg mice with or without systemic immunodeficiency caused by murine retroviral administration (LP-BM5 murine AIDS). Changes in inflammatory cytokine/chemokine mRNA expression was complex and dependent upon expression of gp120 protein, immunodeficiency status, brain region (hippocampus, frontal lobe, or striatum), and age. Gp120 expression reduced hippocampal synaptophysin expression but did not affect animals’ learning/memory on the spontaneous T-maze test in our experimental conditions. Our results emphasize the critical role of the neuroinflammatory micro-environment and the peripheral immune system context in which gp120 acts. Multiple factors, particularly system-level differences in the immune response of different brain regions, need to be considered when developing treatment for HAND.

Graphical Abstract

HIV 影响着全世界 3700 万人，无论是否接受抗病毒治疗，其中 25-69% 的人都会患上 HIV 相关的神经认知障碍 (HAND)。大脑的艾滋病毒感染会降低认知功能，扰乱/损害学习和记忆，并降低受影响者的生活质量。HIV 引起的神经炎症与 gp120 和 Tat 等病毒蛋白有关，即使在外周病毒血症计数较低的患者中，这些蛋白在中枢神经系统中仍然升高。在这项研究中，我们通过检查 gp120tg 小鼠的神经炎症标志物，研究了 gp120 对免疫缺陷与免疫功能正常状态下神经炎症的影响，这些小鼠患有或不患有由鼠逆转录病毒给药引起的全身性免疫缺陷（LP-BM5 鼠艾滋病）。炎症细胞因子/趋化因子 mRNA 表达的变化是复杂的，并且取决于 gp120 蛋白的表达、免疫缺陷状态、大脑区域（海马、额叶或纹状体）和年龄。在我们的实验条件下，Gp120 表达减少海马突触素表达，但不影响动物在自发 T 迷宫测试中的学习/记忆。我们的结果强调了 gp120 发挥作用的神经炎症微环境和外周免疫系统环境的关键作用。在开发 HAND 治疗方法时，需要考虑多种因素，特别是不同大脑区域免疫反应的系统水平差异。

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