Persichini Tiziana, Mastrantonio Roberta, Del Matto Silvia, Palomba Letizia, Cantoni Orazio, Colasanti Marco
Department of Sciences, University Roma Tre, Rome 00146, Italy.
Department of Sciences, University Roma Tre, Rome 00146, Italy.
Free Radic Biol Med. 2014 Sep;74:14-20. doi: 10.1016/j.freeradbiomed.2014.06.009. Epub 2014 Jun 19.
HIV-associated neurocognitive disorder (HAND) is a common cognitive impairment in AIDS that affects 15 to 50% of adults infected with human immunodeficiency virus (HIV). Excessive amounts of nitric oxide (NO), as produced by inducible NO synthase (iNOS) upon exposure of activated microglia and astrocytes to cytokines and/or viral proteins (e.g., HIV tat and gp120), are assumed to contribute to neuronal abnormalities in HAND. Evidence exists supporting the notion that iNOS induction takes place after an early decline in physiological NO levels (i.e., NO released by constitutive NOS). Here, we demonstrate that HIV-1 gp120 is able to inhibit neuronal NOS through a cytosolic phospholipase A2 (cPLA2)-dependent arachidonic acid (AA) production, this response being critical for allowing activation of the transcriptional factor NF-κB and subsequent iNOS and interleukin-1β transcription in astroglial cells. In this context, AA seems to act as an upstream proinflammatory effector. In view of the pathogenic role of cPLA2 in HAND, a deeper insight into the molecular and cellular mechanisms of its modulation may be helpful in finding new drugs to manage cognitive impairment in HIV-1 patients.
人类免疫缺陷病毒相关神经认知障碍（HAND）是艾滋病中一种常见的认知障碍，影响着15%至50%的人类免疫缺陷病毒（HIV）感染成人。诱导型一氧化氮合酶（iNOS）在活化的小胶质细胞和星形胶质细胞暴露于细胞因子和/或病毒蛋白（如HIV反式激活蛋白tat和糖蛋白120）时产生过量的一氧化氮（NO），被认为是导致HAND患者神经元异常的原因。有证据支持这样的观点，即iNOS的诱导发生在生理性NO水平（即组成型NOS释放的NO）早期下降之后。在此，我们证明HIV-1糖蛋白120能够通过依赖胞质磷脂酶A2（cPLA2）的花生四烯酸（AA）生成来抑制神经元型一氧化氮合酶，这种反应对于允许转录因子NF-κB激活以及随后星形胶质细胞中iNOS和白细胞介素-1β的转录至关重要。在这种情况下，AA似乎作为一种上游促炎效应物。鉴于cPLA2在HAND中的致病作用，更深入地了解其调节的分子和细胞机制可能有助于找到治疗HIV-1患者认知障碍的新药。
