Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Room 255, Philadelphia, PA 19107, USA.
Exp Neurol. 2010 Jan;221(1):231-45. doi: 10.1016/j.expneurol.2009.11.004. Epub 2009 Nov 11.
HIV-1 gp120 neurotoxicity and oxidant injury are well documented, but consequent neuroinflammation is less understood. Rat caudate-putamens (CPs) were challenged with 100-500 ng HIV-1BaL gp120, with or without prior rSV40-delivered superoxide dismutase or glutathione peroxidase. CD11b-positive microglia were increased 1 day post-challenge; Iba-1- and ED1-positive cells peaked at 7 days and 14 days. Astrocyte infiltration was maximal at 7-14 days. MIP-1alpha was produced immediately, mainly by neurons. ED1- and GFAP-positive cells correlated with neuron loss and gp120 dose. We also tested the effect of more chronic gp120 exposure on neuroinflammation using an experimental model of continuing gp120 exposure. SV(gp120), a recombinant SV40-derived gene transfer vector was inoculated into the rat CP, leading to chronic expression of gp120, ongoing apoptosis in microglia and neurons, and oxidative stress. Increase in microglia and astrocytes was seen following intra-CP SV(gp120) injection, suggesting that continuing gp120 production increased neuroinflammation. SV(SOD1) or SV(GPx1) significantly reduced MIP-1alpha and limited neuroinflammation following gp120 administration into the CP, as well as microglia and astrocytes proliferation after injection of SV(gp120) in the striatum. Thus, gp120-induced CNS injury, neuron loss and inflammation may be mitigated by antioxidant gene delivery.
HIV-1 gp120 的神经毒性和氧化剂损伤已有充分的记录，但后续的神经炎症了解较少。用 100-500ng HIV-1BaL gp120 对大鼠尾壳核（CP）进行了挑战，有或没有预先用 rSV40 传递的超氧化物歧化酶或谷胱甘肽过氧化物酶。CD11b 阳性的小胶质细胞在挑战后 1 天增加；Iba-1 和 ED1 阳性细胞在第 7 天和第 14 天达到峰值。星形胶质细胞浸润在第 7-14 天达到最大值。MIP-1alpha 立即产生，主要由神经元产生。ED1 和 GFAP 阳性细胞与神经元丢失和 gp120 剂量相关。我们还使用继续 gp120 暴露的实验模型测试了更慢性 gp120 暴露对神经炎症的影响。SV(gp120)是一种重组 SV40 衍生的基因转移载体，接种到大鼠 CP 中，导致 gp120 持续表达，小胶质细胞和神经元持续凋亡，以及氧化应激。在 CP 中 SV(gp120)注射后观察到小胶质细胞和星形胶质细胞增加，表明持续的 gp120 产生增加了神经炎症。SV(SOD1)或 SV(GPx1)在 CP 中给予 gp120 后显著降低了 MIP-1alpha，并限制了神经炎症，以及 SV(gp120)在纹状体注射后小胶质细胞和星形胶质细胞的增殖。因此，抗氧化基因传递可能减轻 gp120 诱导的中枢神经系统损伤、神经元丢失和炎症。
