Institute of Pharmacology, Catholic University Medical School, Rome, Italy.
J Neurochem. 2012 Jan;120(1):106-14. doi: 10.1111/j.1471-4159.2011.07549.x. Epub 2011 Nov 17.
Despite important clinical benefits of the highly active antiretroviral therapy, neurological disorders affect approximately 50% of AIDS patients. In the brain, infected microglia release pro-inflammatory mediators as well as human immunodeficiency virus type 1 (HIV-1) proteins, like the envelope protein gp120, that sustain inflammation and mediate neuronal damage. Gp120 allows the virus entry in the host cells via binding to the CD4 receptor together with a specific co-receptor (CCR5/CXCR4). The antiretroviral drug maraviroc is a CCR5 receptor antagonist, approved for the treatment of HIV-experienced patients. By interfering with a chemokine receptor, highly expressed in microglia, maraviroc has the potential to modulate their activation during HIV-1 infection. To test this hypothesis, primary cultures of rat cortical microglia were activated by gp120. Gp120(CN54) , a protein derived by macrophage (M)-tropic viruses, showed strong pro-inflammatory action, thus it was used to test the effects of maraviroc. The latter displayed opposite effects, depending on whether or not interferon-γ (IFNγ) was also present in the system. IFNγ significantly enhanced gp120 proinflammatory activity, possibly via up-regulation of CCR5 receptor expression. In this experimental paradigm, maraviroc significantly increased microglial activation, thus suggesting that its chronic use can exacerbate neuronal pathology, especially in HIV-experienced patients with higher cerebral IFNγ levels.
尽管高效抗逆转录病毒疗法具有重要的临床益处，但神经系统疾病仍影响着约 50%的艾滋病患者。在大脑中，受感染的小胶质细胞释放促炎介质以及人类免疫缺陷病毒 1 型（HIV-1）蛋白，如包膜蛋白 gp120，这些物质维持炎症并介导神经元损伤。gp120 通过与 CD4 受体结合并与特定的共受体（CCR5/CXCR4）结合，允许病毒进入宿主细胞。抗逆转录病毒药物马拉维若（maraviroc）是一种 CCR5 受体拮抗剂，已被批准用于治疗 HIV 感染经验丰富的患者。通过干扰趋化因子受体，该受体在小胶质细胞中高度表达，马拉维若（maraviroc）有可能在 HIV-1 感染期间调节其激活。为了验证这一假设，用 gp120 激活大鼠皮质小胶质细胞的原代培养物。gp120(CN54)是一种源自巨噬细胞（M）嗜性病毒的蛋白，显示出强烈的促炎作用，因此被用于测试马拉维若（maraviroc）的作用。后者显示出相反的效果，这取决于干扰素-γ（IFNγ）是否也存在于系统中。IFNγ 显著增强了 gp120 的促炎活性，可能是通过上调 CCR5 受体的表达。在这种实验模型中，马拉维若（maraviroc）显著增加了小胶质细胞的激活，因此表明其慢性使用可能会加重神经元病理学，特别是在 HIV 感染经验丰富且大脑 IFNγ 水平较高的患者中。
