Departamento de Neurología, Escuela de Medicina and Centro Interdisciplinario de Neurociencias, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile.
Institute of Biomedical Sciences, Faculty of Health Sciences, Universidad Autónoma de Chile, Santiago 8910060, Chile.
Int J Mol Sci. 2020 Apr 3;21(7):2503. doi: 10.3390/ijms21072503.
At least half of human immunodeficiency virus (HIV)-infected individuals suffer from a wide range of cognitive, behavioral and motor deficits, collectively known as HIV-associated neurocognitive disorders (HAND). The molecular mechanisms that amplify damage within the brain of HIV-infected individuals are unknown. Recently, we described that HIV augments the opening of connexin-43 (Cx43) hemichannels in cultured human astrocytes, which result in the collapse of neuronal processes. Whether HIV soluble viral proteins such as gp120, can regulate hemichannel opening in astrocytes is still ignored. These channels communicate the cytosol with the extracellular space during pathological conditions. We found that gp120 enhances the function of both Cx43 hemichannels and pannexin-1 channels in mouse cortical astrocytes. These effects depended on the activation of IL-1β/TNF-α, p38 MAP kinase, iNOS, cytoplasmic Ca and purinergic signaling. The gp120-induced channel opening resulted in alterations in Ca dynamics, nitric oxide production and ATP release. Although the channel opening evoked by gp120 in astrocytes was reproduced in ex vivo brain preparations, these responses were heterogeneous depending on the CA1 region analyzed. We speculate that soluble gp120-induced activation of astroglial Cx43 hemichannels and pannexin-1 channels could be crucial for the pathogenesis of HAND.
至少有一半的人类免疫缺陷病毒（HIV）感染者患有广泛的认知、行为和运动障碍，统称为 HIV 相关神经认知障碍（HAND）。导致 HIV 感染者大脑损伤扩大的分子机制尚不清楚。最近，我们描述了 HIV 增强了培养的人星形胶质细胞中连接蛋白 43（Cx43）半通道的开放，导致神经元过程崩溃。HIV 可溶性病毒蛋白（如 gp120）是否可以调节星形胶质细胞中的半通道开放仍然未知。这些通道在病理条件下将细胞质与细胞外空间连通。我们发现 gp120 增强了小鼠皮质星形胶质细胞中 Cx43 半通道和 Pannexin-1 通道的功能。这些效应依赖于 IL-1β/TNF-α、p38 MAP 激酶、iNOS、细胞质 Ca 和嘌呤能信号的激活。gp120 诱导的通道开放导致 Ca 动力学、一氧化氮产生和 ATP 释放的改变。尽管 gp120 在星形胶质细胞中诱导的通道开放在离体脑标本中得到重现，但这些反应因分析的 CA1 区域而异。我们推测，可溶性 gp120 诱导的星形胶质细胞 Cx43 半通道和 Pannexin-1 通道的激活可能对 HAND 的发病机制至关重要。
