Meulendyke Kelly A, Queen Suzanne E, Engle Elizabeth L, Shirk Erin N, Liu Jiayang, Steiner Joseph P, Nath Avindra, Tarwater Patrick M, Graham David R, Mankowski Joseph L, Zink M Christine
Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, 733 North Broadway Street, MRB 819, Baltimore, MD, 21205, USA.
J Neurovirol. 2014 Dec;20(6):591-602. doi: 10.1007/s13365-014-0283-1. Epub 2014 Sep 17.
Effective combined antiretroviral therapy (cART) in HIV-infected patients has made HIV a treatable infection; however, debilitating HIV-associated neurocognitive disorders (HAND) can still affect approximately 50% of HIV-infected individuals even under cART. While cART has greatly reduced the prevalence of the most severe form of HAND, milder forms have increased in prevalence, leaving the total proportion of HIV-infected individuals suffering from HAND relatively unchanged. In this study, an in vitro drug screen identified fluconazole and paroxetine as protective compounds against HIV gp120 and Tat neurotoxicity. Using an accelerated, consistent SIV/macaque model of HIV-associated CNS disease, we tested the in vivo neuroprotective capabilities of combination fluconazole/paroxetine (FluPar) treatment. FluPar treatment protected macaques from SIV-induced neurodegeneration, as measured by neurofilament light chain in the CSF, APP accumulation in axons, and CaMKIIα in the frontal cortex, but did not significantly reduce markers of neuroinflammation or plasma or CNS viral loads. Since HIV and SIV neurodegeneration is often attributed to accompanying neuroinflammation, this study provides proof of concept that neuroprotection can be achieved even in the face of ongoing neuroinflammation and viral replication.
对感染HIV的患者进行有效的联合抗逆转录病毒疗法（cART）已使HIV感染成为可治疗的疾病；然而，即使在接受cART治疗的情况下，使人虚弱的HIV相关神经认知障碍（HAND）仍可能影响约50%的HIV感染者。虽然cART已大大降低了最严重形式的HAND的患病率，但较轻形式的患病率却有所增加，使得感染HIV且患有HAND的个体的总体比例相对保持不变。在本研究中，一项体外药物筛选确定氟康唑和帕罗西汀为针对HIV gp120和Tat神经毒性的保护性化合物。我们使用一种加速、一致的HIV相关中枢神经系统疾病的SIV/猕猴模型，测试了氟康唑/帕罗西汀联合治疗（FluPar）的体内神经保护能力。通过脑脊液中的神经丝轻链、轴突中的APP积累以及额叶皮质中的CaMKIIα来衡量，FluPar治疗保护猕猴免受SIV诱导的神经退行性变，但并未显著降低神经炎症标志物或血浆及中枢神经系统病毒载量。由于HIV和SIV神经退行性变通常归因于伴随的神经炎症，本研究提供了概念验证，即即使面对持续的神经炎症和病毒复制，也可实现神经保护。
