Mechanisms underlying dysregulated neuroimmune signaling and neuronal dysfunction in HIV (+) individuals with cART and cocaine

摘要： 持续性神经炎症和突触树突起损伤是NeuroHIV的两个特征。 导致这些病理变化的因素包括低水平残留的艾滋病毒复制/艾滋病毒蛋白和/或 CART本身的毒性。众所周知，药物滥用，特别是可卡因滥用，是一种常见的共病。 艾滋病毒感染的可能性。耐人寻味的是，可卡因还被证明可以通过其 对免疫细胞的直接影响，如小胶质细胞和/或通过降低CART的有效性。因此，它可以是 设想在中枢神经系统内，艾滋病毒蛋白、滥用药物和CART的组合创造了一个有毒的环境 促进通过促炎作用加重神经炎症和异常的神经胶质细胞-神经元串扰 调解人。调控失调的神经免疫信号转导通路的详细分子途径 然而，随后的突触树突损伤仍然难以捉摸。我们的初步研究显示： 1)HIVTAT可通过NLRP3炎症体信号通路增加小胶质细胞的激活；2)可卡因激活 小胶质细胞通过失调的自噬途径，&3)临床使用的抗逆转录病毒鸡尾酒(TFV， FTC、DTG)损伤小胶质细胞溶酶体功能，导致其激活。此外，我们还 NLRP3炎症体激活途径的产物IL1β上调谷氨酸 受体离子型NMDAs(GRINS)和伴随而来的初级神经元的脊髓密度降低。这个 因此，这一应用的前提是HIV TAT、可卡因和ARV的组合可以通过 NLRP3炎症小体和自噬途径，以及IL-1β的释放增加。反过来, 会导致神经元功能障碍。使用体外和体内(HIV转基因大鼠)方法，我们将 通过三个具体目标检验假设-SA1：调查TAT背后的分子机制(S)， 可卡因、抗逆转录病毒药物(3种药物方案)介导的小胶质细胞体外激活；SA2：分子研究 IL_1β诱导神经元兴奋性毒性的机制(S)：体内验证NLRP3的变化 炎症体和自噬信号以及lncRNA MALAT1/NF-κB/GRINS轴与 给予可卡因和CAV的HIV-TG大鼠的行为缺陷。两位经验丰富的专业人士(郭和布赫博士)将 共同领导这个项目，以完成建议的目标。此R01应用程序响应RFA-MH-18-610 题为《HIV诱导的中枢神经系统(CNS)中神经元回路、受体和网络的改变》 旨在探索神经免疫功能失调的分子机制。 由HIV蛋白、滥用药物和CRAT引起的信号影响神经元受体的功能。

Abstract: Sustained neuroinflammation & synaptodendritic injury are the two hallmark features underlying NeuroHIV. Factors contributing to these pathological changes include low-level residual HIV replication/HIV proteins and/or toxicity of cART itself. It is well-recognized that drug abuse, specifically cocaine abuse, is a common comorbidity of HIV infection. Intriguingly, cocaine has also been shown to exacerbate neuroinflammation either through its direct effects on immune cells, such as microglia and/or by decreasing the effectiveness of cART. It can thus be envisioned that within the CNS, combinations of HIV proteins, abused drugs and cART create a toxic milieu promoting exacerbated neuroinflammation and abnormal glial-neuronal cross-talk via the pro-inflammatory mediators. The detailed molecular pathways underlying the dysregulated neuroimmune signaling and subsequent synaptodendritic injury, however, remain elusive. Our preliminary studies have demonstrated that: 1) HIV TAT can increase microglial activation via the NLRP3 inflammasome signaling; 2) cocaine activates microglia via the dysregulated autophagy pathway, & 3) Combination of clinically used antiretroviral cocktail (TFV, FTC, DTG) impaired microglial lysosome functions leading to their activation. Furthermore, we also demonstrated that IL1β, product of the NLRP3 inflammasome activation pathway, upregulated the glutamate receptor ionotropic NMDAs (GRINS) and concomitantly decreased spine density in primary neurons. The premise of this application thus is that combinations of HIV TAT, cocaine & ARVs can activate microglia via the NLRP3 inflammasome & autophagy pathways, and that the increased release of IL1β. In turn, contributes to neuronal dysfunction. Using both in vitro and in vivo (HIV transgenic rats) approaches we will test the hypothesis via three specific aims - SA1: Investigate the molecular mechanism(s) underlying TAT, cocaine, & ARVs (3 drug regimen)-mediated activation of microglia in vitro; SA2: Investigate the molecular mechanism(s) underlying IL1β-induced neuronal excitotoxicity & SA3: Validate in vivo the changes in NLRP3 inflammasome and autophagy signaling and also lncRNA malat1/NF-κB/GRINs axis in conjunction with behavioral deficits in HIV-Tg rats administered cocaine and cARV. Two experienced PIs (Drs. Guo & Buch) will co-lead this project to accomplish the proposed goals. This R01 application, in response to RFA-MH-18-610 titled “Altered neuronal circuits, receptors and networks in HIV-induced Central Nervous System (CNS) dysfunction,” aims to explore the molecular mechanisms underlying how the dysregulated neuroimmune signaling caused by HIV proteins, drugs of abuse, & cRAT impacts the function of neuronal receptors.