Abstract：
The activity of HIV-1 and its viral proteins within the central nervous system (CNS) is responsible for a wide array of neuropathological effects, resulting in a spectrum of neurocognitive deficits defined as HIV-associated neurocognitive disorders (HAND). Amongst the various viral proteins, the transactivator of transcription (Tat) remains detectable even with effective antiretroviral therapy (ART) and suppressed viremia, highlighting the significance of this protein in the modern ART era. Tat has been extensively researched in both fundamental and clinical settings due to its role in neuroinflammation, neuronal damage, and neurocognitive impairment amongst people living with HIV (PLHIV). To date, numerous fundamental studies have explored Tat-induced neuroinflammation. However, there is no clear consensus on the most frequently studied inflammatory markers or the consistency in the levels of these Tat-induced inflammatory marker levels across different studies. Therefore, we conducted a scoping review of studies investigating Tat-induced neuroinflammation. We conducted searches in PubMed, Scopus, and Web of Science databases using a search protocol tailored specifically to adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for scoping reviews (PRISMA-ScR) guidelines. From the 22 included studies, findings suggest that the HIV-1 Tat protein amplifies levels of neuroinflammatory markers. Amongst the vast array of inflammatory markers explored in the included studies, consistent results point to higher levels of CCL2, IL-6, IL-8, and TNF-α in primary cells and cell lines exposed to or transfected with HIV-1 Tat. These markers are regulated by key inflammatory pathways, such as the extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) pathway, the phosphatidylinositol 3-kinase (PI3K) pathway, the p38 MAPK pathway, and nuclear factor-kB (NF-kB). Furthermore, Tat has been shown to induce neuronal apoptosis, both directly and indirectly. With regards to study designs, utilizing full-length Tat101 at concentrations ranging from 100 to 1000 ng/ml and durations of 24 and 48 h appears optimal for investigating Tat-induced neuroinflammation. In this context, we highlight specific inflammatory markers and pathways that are potentially pivotal in Tat-induced neuroinflammation and subsequent neuronal damage. A deeper investigation into these markers and pathways is crucial to better understand their roles in the development of HAND.
摘要：
HIV-1及其病毒蛋白在中枢神经系统（CNS）中的活性负责广泛的神经病理效应，导致一系列定义为HIV相关神经认知障碍（HAND）的神经认知缺陷。在各种病毒蛋白中，即使使用有效的抗逆转录病毒治疗（ART）和抑制病毒血症，转录反式激活因子（Tat）仍然可以检测到，强调这种蛋白质在现代ART时代的重要性。由于其在神经炎症中的作用，Tat已在基础和临床环境中进行了广泛的研究，神经元损伤，以及HIV感染者（PLHIV）中的神经认知障碍。迄今为止,许多基础研究探索了Tat诱导的神经炎症。然而,在不同研究中,对于最常研究的炎症标志物或这些Tat诱导的炎症标志物水平的一致性没有明确的共识.因此,我们对Tat诱导的神经炎症研究进行了范围综述.我们在PubMed进行了搜索,Scopus,和WebofScience数据库使用专门定制的搜索协议，以遵守用于范围审查的系统审查和荟萃分析（PRISMA-ScR）指南的首选报告项目。从22项纳入的研究中，研究结果表明，HIV-1Tat蛋白会放大神经炎症标志物的水平。在纳入的研究中探索的大量炎症标志物中，一致的结果表明，暴露于或转染HIV-1Tat的原代细胞和细胞系中CCL2，IL-6，IL-8和TNF-α的水平较高。这些标记物受到关键炎症途径的调节，如细胞外信号调节激酶（ERK）1/2丝裂原活化蛋白激酶（MAPK）途径，磷脂酰肌醇3-激酶（PI3K）途径，p38MAPK通路，和核因子-kB(NF-kB)。此外，Tat已被证明能诱导神经元凋亡，直接和间接。关于研究设计，使用浓度范围为100至1000ng/ml的全长Tat101，持续时间为24和48h似乎最适合研究Tat诱导的神经炎症。在这种情况下，我们强调了在Tat诱导的神经炎症和随后的神经元损伤中潜在关键的特异性炎症标志物和通路.对这些标记和途径的深入研究对于更好地了解它们在HAND发育中的作用至关重要。
