Buch Shilpa, Periyasamy Palsamy, Guo Minglei
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
Epigenet Insights. 2018 Oct 14;11:2516865718806904. doi: 10.1177/2516865718806904. eCollection 2018.
Despite the efficacy of combination antiretroviral therapy (cART) in controlling viremia, the central nervous system (CNS) continues to harbor viral reservoirs. The persistence of low-level virus replication leads to the accumulation of early viral proteins, including HIV-1 Transactivator of transcription (HIV-1 Tat) protein. Based on the premise that cART does not impact levels of HIV-1 Tat, and since the CNS is inaccessible to the cART regimens, HIV-1-Tat-mediated neuroinflammation has been implicated as an underlying mediator of HIV-1-associated neurocognitive disorders (HAND). The mechanism(s) underlying the pathogenesis of HAND, however, remain less understood. Understanding the epigenetic/molecular mechanism(s) by which viral proteins such as HIV-1 Tat activate microglia is thus of paramount importance. The study published by Periyasamy et al provides new mechanistic insights into the role of HIV-1-Tat-mediated DNA methylation of miR-124 promoter in regulating microglial activation via the MECP2-STAT3 signaling axis. Furthermore, the authors have also reported that exposure of mouse primary microglial cells to HIV-1 Tat notably increased DNA methylation of primary miR-124-1 and primary miR-124-2 promoters (with no change in primary miR-124-3), resulting in turn to downregulated expression of both primary miR-124-1 and primary miR-124-2 as well as mature miR-124 in mouse primary microglial cells. The authors also examined the involvement of MECP2-STAT3 signaling in HIV-1-Tat-mediated microglial activation. Based on these novel findings, it is evident that dysregulation of miR-124 is involved in the pathogenesis of HAND and that restoration of miR-124 could serve as an adjunctive treatment for dampening neuroinflammation associated with HAND.
尽管联合抗逆转录病毒疗法（cART）在控制病毒血症方面具有疗效，但中枢神经系统（CNS）中仍存在病毒储存库。低水平病毒复制的持续存在导致早期病毒蛋白的积累，包括HIV-1转录激活因子（HIV-1 Tat）蛋白。基于cART不影响HIV-1 Tat水平这一前提，且由于cART方案无法作用于中枢神经系统，HIV-1 Tat介导的神经炎症被认为是HIV-1相关神经认知障碍（HAND）的潜在介导因素。然而，HAND发病机制的潜在机制仍不太清楚。因此，了解HIV-1 Tat等病毒蛋白激活小胶质细胞的表观遗传/分子机制至关重要。Periyasamy等人发表的研究为HIV-1 Tat介导的miR-124启动子DNA甲基化通过MECP2-STAT3信号轴调节小胶质细胞激活的作用提供了新的机制见解。此外，作者还报告说，将小鼠原代小胶质细胞暴露于HIV-1 Tat可显著增加初级miR-124-1和初级miR-124-2启动子的DNA甲基化（初级miR-124-3无变化），进而导致小鼠原代小胶质细胞中初级miR-124-1和初级miR-124-2以及成熟miR-124的表达下调。作者还研究了MECP2-STAT3信号在HIV-1 Tat介导的小胶质细胞激活中的作用。基于这些新发现，很明显miR-124的失调参与了HAND的发病机制，恢复miR-124可作为减轻与HAND相关的神经炎症的辅助治疗方法。
