Mediouni Sonia, Jablonski Joseph, Paris Jason J, Clementz Mark A, Thenin-Houssier Suzie, McLaughlin Jay P, Valente Susana T
Department of Infectious diseases, The Scripps Research Institute, 130 Scripps Way, 3C1, Jupiter, FL 33458, USA.
Curr HIV Res. 2015;13(1):64-79. doi: 10.2174/1570162x13666150121111548.
HIV-1 Tat protein has been shown to have a crucial role in HIV-1-associated neurocognitive disorders (HAND), which includes a group of syndromes ranging from undetectable neurocognitive impairment to dementia. The abuse of psychostimulants, such as cocaine, by HIV infected individuals, may accelerate and intensify neurological damage. On the other hand, exposure to Tat potentiates cocaine-mediated reward mechanisms, which further promotes HAND. Here, we show that didehydro-Cortistatin A (dCA), an analog of a natural steroidal alkaloid, crosses the blood-brain barrier, cross-neutralizes Tat activity from several HIV-1 clades and decreases Tat uptake by glial cell lines. In addition, dCA potently inhibits Tat mediated dysregulation of IL-1β, TNF-α and MCP-1, key neuroinflammatory signaling proteins. Importantly, using a mouse model where doxycycline induces Tat expression, we demonstrate that dCA reverses the potentiation of cocaine-mediated reward. Our results suggest that adding a Tat inhibitor, such as dCA, to current antiretroviral therapy may reduce HIV-1-related neuropathogenesis.
HIV-1反式激活因子蛋白已被证明在与HIV-1相关的神经认知障碍（HAND）中起关键作用，HAND包括从难以检测到的神经认知障碍到痴呆症的一系列综合征。感染HIV的个体滥用精神兴奋剂，如可卡因，可能会加速和加剧神经损伤。另一方面，接触反式激活因子会增强可卡因介导的奖赏机制，这进一步促进了HAND。在此，我们表明，天然甾体生物碱的类似物双脱氢皮质抑素A（dCA）可穿过血脑屏障，交叉中和来自多个HIV-1分支的反式激活因子活性，并减少神经胶质细胞系对反式激活因子的摄取。此外，dCA能有效抑制反式激活因子介导的白细胞介素-1β、肿瘤坏死因子-α和单核细胞趋化蛋白-1（关键的神经炎症信号蛋白）的失调。重要的是，利用强力霉素诱导反式激活因子表达的小鼠模型，我们证明dCA可逆转可卡因介导的奖赏增强作用。我们的结果表明，在当前的抗逆转录病毒疗法中添加一种反式激活因子抑制剂，如dCA，可能会减少与HIV-1相关的神经病理发生。
