Joshi Chaitanya R, Stacy Satomi, Sumien Nathalie, Ghorpade Anuja, Borgmann Kathleen
Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, Fort Worth, TX, United States.
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, United States.
Front Neurol. 2020 Dec 15;11:593188. doi: 10.3389/fneur.2020.593188. eCollection 2020.
Despite effective antiretroviral therapy (ART), mild forms of HIV-associated neurocognitive disorders (HAND) continue to afflict approximately half of all people living with HIV (PLWH). As PLWH age, HIV-associated inflammation perturbs the balance between brain matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs), likely contributing to neuropathogenesis. The MMP/TIMP balance is associated with cognition, learning, and memory, with TIMPs eliciting neuroprotective effects. Dysregulation of the MMP/TIMP balance was evident in the brains of PLWH where levels of TIMP-1, the inducible family member, were significantly lower than non-infected controls, and MMPs were elevated. Here, we evaluated the MMP/TIMP levels in the doxycycline (DOX)-induced glial fibrillary acidic protein promoter-driven HIV-1 transactivator of transcription (Tat) transgenic mouse model. The HIV-1 protein Tat is constitutively expressed by most infected cells, even during ART suppression of viral replication. Many studies have demonstrated indirect and direct mechanisms of short-term Tat-associated neurodegeneration, including gliosis, blood-brain barrier disruption, elevated inflammatory mediators and neurotoxicity. However, the effects of acute vs. prolonged exposure on Tat-induced dysregulation remain to be seen. This is especially relevant for TIMP-1 as expression was previously shown to be differentially regulated in human astrocytes during acute vs. chronic inflammation. In this context, acute Tat expression was induced with DOX intraperitoneal injections over 3 weeks, while DOX-containing diet was used to achieve long-term Tat expression over 6 months. First, a series of behavior tests evaluating arousal, ambulation, anxiety, and cognition was performed to examine impairments analogous to those observed in HAND. Next, gene expression of components of the MMP/TIMP axis and known HAND-relevant inflammatory mediators were assessed. Altered anxiety-like, motor and/or cognitive behaviors were observed in Tat-induced (iTat) mice. Gene expression of MMPs and TIMPs was altered depending on the duration of Tat expression, which was independent of the HIV-associated neuroinflammation typically implicated in MMP/TIMP regulation. Collectively, we infer that HIV-1 Tat-mediated dysregulation of MMP/TIMP axis and behavioral changes are dependent on duration of exposure. Further, prolonged Tat expression demonstrates a phenotype comparable to asymptomatic to mild HAND manifestation in patients.
尽管有有效的抗逆转录病毒疗法（ART），轻度形式的HIV相关神经认知障碍（HAND）仍继续折磨着约一半的HIV感染者（PLWH）。随着PLWH年龄的增长，HIV相关炎症扰乱了脑基质金属蛋白酶（MMPs）与其金属蛋白酶组织抑制剂（TIMPs）之间的平衡，这可能是神经发病机制的原因之一。MMP/TIMP平衡与认知、学习和记忆相关，TIMPs具有神经保护作用。在PLWH的大脑中，MMP/TIMP平衡失调很明显，其中诱导型家族成员TIMP-1的水平显著低于未感染的对照组，而MMPs则升高。在此，我们评估了强力霉素（DOX）诱导的胶质纤维酸性蛋白启动子驱动的HIV-1转录激活因子（Tat）转基因小鼠模型中的MMP/TIMP水平。即使在ART抑制病毒复制期间，大多数受感染细胞也会持续表达HIV-1蛋白Tat。许多研究已经证明了短期Tat相关神经变性的间接和直接机制，包括胶质增生、血脑屏障破坏、炎症介质升高和神经毒性。然而，急性暴露与长期暴露对Tat诱导的失调的影响仍有待观察。这对于TIMP-1尤其相关，因为先前的研究表明，在急性与慢性炎症期间，人星形胶质细胞中TIMP-1的表达受到不同的调节。在这种情况下，通过腹腔注射DOX持续3周诱导急性Tat表达，而使用含DOX的饮食在6个月内实现长期Tat表达。首先，进行了一系列评估觉醒、行走、焦虑和认知的行为测试，以检查类似于HAND中观察到的损伤。接下来，评估了MMP/TIMP轴的组成部分和已知的与HAND相关的炎症介质的基因表达。在Tat诱导（iTat）小鼠中观察到了焦虑样、运动和/或认知行为的改变。MMPs和TIMPs的基因表达根据Tat表达的持续时间而改变，这与通常参与MMP/TIMP调节的HIV相关神经炎症无关。总的来说，我们推断HIV-1 Tat介导的MMP/TIMP轴失调和行为变化取决于暴露持续时间。此外，长期Tat表达表现出与患者无症状至轻度HAND表现相当的表型。
