Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Department of Neurology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
mBio. 2020 Dec 8;11(6):e02939-20. doi: 10.1128/mBio.02939-20.
Successful treatment of HIV-infected patients with combinational antiretroviral therapies (cART) can now prolong patients' lives to nearly normal life spans. However, the new challenge faced by many of those HIV-infected patients is chronic neuroinflammation and neurotoxicity that often leads to HIV-associated neurocognitive disorders (HAND). However, the mechanism of neuropathogenesis underlying HAND, especially in those who are under cART, is not well understood. HAND is typically characterized by HIV-mediated glial neuroinflammation and neurotoxicity. However, the severity of HAND does not always correlate with HIV-1 viral load but, rather, with the extent of glial activation, suggesting that other HIV-associated factors might contribute to HAND. HIV-1 viral protein R (Vpr) could be one of those viral factors because of its association with neuroinflammation and neurotoxicity. The objective of this study was to delineate the specific roles of HIV-1 infection and Vpr in the activation of neuroinflammation and neurotoxicity, and the possible relationships with the Sur1-Trpm4 channel that contributes to neuroinflammation and neuronal death. Here, we show that HIV-1 expression correlates with activation of proinflammatory markers (TLR4, TNF-α, and NF-κB) and the Sur1-Trpm4 channel in astrocytes of HIV-infected postmortem human and transgenic Tg26 mouse brain tissues. We further show that Vpr alone activates the same set of proinflammatory markers and Sur1 in a glioblastoma SNB19 cell line that is accompanied by apoptosis. The Sur1 inhibitor glibenclamide significantly reduced Vpr-induced apoptosis. Together, our data suggest that HIV-1 Vpr-induced proinflammatory response and apoptosis are mediated at least in part through the Sur1-Trpm4 channel in astrocytes. Effective antiretroviral therapies can now prolong patients' lives to nearly normal life span. The current challenge faced by many HIV-infected patients is chronic neuroinflammation and neurotoxicity that contributes to HIV-associated neurocognitive disorders (HAND). We show here that the expression of HIV-1 infection and Vpr correlates with the activation of proinflammatory markers (Toll-like receptor 4 [TLR4], tumor necrosis factor alpha [TNF-α], and NF-κB) and the sulfonylurea receptor 1 (Sur1)-transient receptor potential melastatin 4 (Trpm4) channel in astrocytes of brain tissues. We further show that an FDA-approved Sur1 inhibitory drug called glibenclamide significantly ameliorates apoptotic astrocytic cell death caused by HIV-1 Vpr, which could potentially open the possibility of repurposing glibenclamide for treating HAND.
成功的抗逆转录病毒疗法（cART）可以延长 HIV 感染者的生命，使他们的寿命接近正常。然而，许多 HIV 感染者面临的新挑战是慢性神经炎症和神经毒性，这通常导致与 HIV 相关的认知障碍（HAND）。然而，HAND 潜在的神经发病机制，特别是在接受 cART 的患者中，尚未得到很好的理解。HAND 的特征通常是 HIV 介导的神经胶质炎症和神经毒性。然而，HAND 的严重程度并不总是与 HIV-1 病毒载量相关，而是与神经胶质激活的程度相关，这表明其他与 HIV 相关的因素可能导致 HAND。HIV-1 病毒蛋白 R（Vpr）可能是这些病毒因素之一，因为它与神经炎症和神经毒性有关。本研究的目的是阐明 HIV-1 感染和 Vpr 在神经炎症和神经毒性激活中的具体作用，以及与有助于神经炎症和神经元死亡的 Sur1-Trpm4 通道的可能关系。在这里，我们显示 HIV-1 的表达与 HIV 感染者死后人和转基因 Tg26 小鼠脑组织中星形胶质细胞中促炎标志物（TLR4、TNF-α 和 NF-κB）和 Sur1-Trpm4 通道的激活相关。我们进一步显示，Vpr 单独激活了相同的一组促炎标志物和神经胶质瘤 SNB19 细胞系中的 Sur1，同时伴有细胞凋亡。Sur1 抑制剂格列本脲可显著减少 Vpr 诱导的细胞凋亡。总之，我们的数据表明，HIV-1 Vpr 诱导的炎症反应和细胞凋亡至少部分通过星形胶质细胞中的 Sur1-Trpm4 通道介导。有效的抗逆转录病毒疗法现在可以将患者的生命延长至接近正常寿命。许多 HIV 感染者目前面临的挑战是慢性神经炎症和神经毒性，这导致与 HIV 相关的认知障碍（HAND）。我们在这里显示，HIV-1 感染和 Vpr 的表达与促炎标志物（Toll 样受体 4 [TLR4]、肿瘤坏死因子-α [TNF-α] 和 NF-κB）和星形胶质细胞中的磺酰脲受体 1（Sur1）-瞬时受体电位 melastatin 4（Trpm4）通道的激活相关。我们进一步表明，一种已获美国食品和药物管理局批准的 Sur1 抑制剂称为格列本脲可显著改善由 HIV-1 Vpr 引起的星形胶质细胞凋亡性细胞死亡，这可能为重新利用格列本脲治疗 HAND 开辟可能性。
