Division of Biomedical Sciences, School of Medicine, University of California, Riverside, 900 University Ave, Riverside, CA, 92521, USA; Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
Division of Biomedical Sciences, School of Medicine, University of California, Riverside, 900 University Ave, Riverside, CA, 92521, USA.
Brain Behav Immun. 2024 May;118:1-21. doi: 10.1016/j.bbi.2024.02.014. Epub 2024 Feb 13.
Human immunodeficiency virus-1 (HIV-1) infects the central nervous system (CNS) and causes HIV-associated neurocognitive disorders (HAND) in about half of the population living with the virus despite combination anti-retroviral therapy (cART). HIV-1 activates the innate immune system, including the production of type 1 interferons (IFNs) α and β. Transgenic mice expressing HIV-1 envelope glycoprotein gp120 (HIVgp120tg) in the CNS develop memory impairment and share key neuropathological features and differential CNS gene expression with HIV patients, including the induction of IFN-stimulated genes (ISG). Here we show that knocking out IFNβ (IFNβKO) in HIVgp120tg and non-tg control mice impairs recognition and spatial memory, but does not affect anxiety-like behavior, locomotion, or vision. The neuropathology of HIVgp120tg mice is only moderately affected by the KO of IFNβ but in a sex-dependent fashion. Notably, in cerebral cortex of IFNβKO animals presynaptic terminals are reduced in males while neuronal dendrites are reduced in females. The IFNβKO results in the hippocampal CA1 region of both male and female HIVgp120tg mice in an ameliorated loss of neuronal presynaptic terminals but no protection of neuronal dendrites. Only female IFNβ-deficient HIVgp120tg mice display diminished microglial activation in cortex and hippocampus and increased astrocytosis in hippocampus compared to their IFNβ-expressing counterparts. RNA expression for some immune genes and ISGs is also affected in a sex-dependent way. The IFNβKO abrogates or diminishes the induction of MX1, DDX58, IRF7 and IRF9 in HIVgp120tg brains of both sexes. Expression analysis of neurotransmission related genes reveals an influence of IFNβ on multiple components with more pronounced changes in IFNβKO females. In contrast, the effects of IFNβKO on MAPK activities are independent of sex with pronounced reduction of active ERK1/2 but also of active p38 in the HIVgp120tg brain. In summary, our findings show that the absence of IFNβ impairs memory dependent behavior and modulates neuropathology in HIVgp120tg brains, indicating that its absence may facilitate development of HAND. Moreover, our data suggests that endogenous IFNβ plays a vital role in maintaining neuronal homeostasis and memory function.
人类免疫缺陷病毒 1（HIV-1）感染中枢神经系统（CNS），并导致约一半的病毒感染者出现与 HIV 相关的神经认知障碍（HAND），尽管进行了联合抗逆转录病毒治疗（cART）。HIV-1 激活先天免疫系统，包括产生 I 型干扰素（IFN）α和β。在中枢神经系统中表达 HIV-1 包膜糖蛋白 gp120（HIVgp120tg）的转基因小鼠会出现记忆障碍，并与 HIV 患者共享关键的神经病理学特征和中枢神经系统基因表达，包括诱导 IFN 刺激基因（ISG）。在这里，我们表明，在 HIVgp120tg 和非 tg 对照小鼠中敲除 IFNβ（IFNβKO）会损害识别和空间记忆，但不会影响焦虑样行为、运动或视力。IFNβKO 对 HIVgp120tg 小鼠的神经病理学影响仅适度，但具有性别依赖性。值得注意的是，在 IFNβKO 动物的大脑皮层中，雄性的突触前末梢减少，而雌性的神经元树突减少。IFNβKO 导致雄性和雌性 HIVgp120tg 小鼠的海马 CA1 区神经元突触前末梢的丢失减轻，但对神经元树突没有保护作用。只有雌性 IFNβ 缺陷的 HIVgp120tg 小鼠在皮层和海马体中显示出小胶质细胞激活减少，而在海马体中星形胶质细胞增生增加，与表达 IFNβ 的对照小鼠相比。一些免疫基因和 ISG 的 RNA 表达也以性别依赖的方式受到影响。IFNβKO 消除或减少了两性 HIVgp120tg 大脑中 MX1、DDX58、IRF7 和 IRF9 的诱导。神经传递相关基因的表达分析显示 IFNβ 对多个成分有影响，IFNβKO 雌性的变化更为明显。相比之下，IFNβKO 对 MAPK 活性的影响与性别无关，HIVgp120tg 大脑中 ERK1/2 和 p38 的活性明显降低。总之，我们的研究结果表明，IFNβ 的缺失会损害 HIVgp120tg 大脑中依赖于记忆的行为，并调节其神经病理学，表明其缺失可能促进 HAND 的发展。此外，我们的数据表明，内源性 IFNβ 在维持神经元内稳态和记忆功能方面发挥着至关重要的作用。
