Peripheral neurotoxicity by the HIV-1 coat protein gp120

描述（由申请人提供）：HIV相关感觉神经病变（HIV-SN）现在被认为是HIV感染最常见的神经系统并发症，严重影响三分之一的艾滋病患者，包括儿童和成人。迄今为止，很少有人关注这种非常痛苦的疾病的发病机制，目前还没有有效的治疗方法。在病理学上，HIV-SN的特征在于背根神经节（DRG）感觉神经元的损失、由HIV感染的巨噬细胞浸润DRG和“垂死的"感觉神经病。与HIV痴呆的情况类似，HIV神经元感染很少发生在HIV-SN患者的DRG中。因此，我们假设，DRG神经元的损失和感觉轴突病变中看到的HIV-SN的结果从神经毒性的可溶性介质释放的HIV感染的巨噬细胞存在于这些患者的DRG。这些介质包括分泌的病毒蛋白，如HIV-1包膜糖蛋白gp 120，我们最近已经表明，这是一个非常有效的神经毒素在大鼠胚胎DRG文化。我们推测，HIV感染的巨噬细胞在DRG中释放的gp 120通过连接神经元、巨噬细胞和雪旺细胞上的趋化因子受体引起直接和间接的外周神经毒性。此外，由于神经病理学的严重程度并不总是反映疼痛的程度，所以占主导地位的艾滋病毒-SN的神经病学，我们认为，gp 120可能有助于神经病理性疼痛的发病机制，直接激活伤害性神经元。本项目旨在研究人胎儿背根神经节培养物中gp 120的神经毒性，并阐明导致这种神经毒性的发病机制，以便设计治疗策略。我们的提议的一个主要优势是我们使用人体组织来研究一种只影响人类的疾病。

DESCRIPTION (provided by applicant): HIV-associated sensory neuropathy (HIV-SN) is now recognized as the most common neurological complication of HIV infection, symptomatically affecting one-third of AIDS patients, including children and adults. Little attention has so far been devoted to exploring the pathogenesis of this very painful disorder, which presently has no effective treatment. Pathologically, HIV-SN is characterized by loss of Dorsal Root Ganglion (DRG) sensory neurons, DRG infiltration by HIV-infected macrophages, and a 'dying back' sensory neuropathy. Akin to the situation in HIV dementia, neuronal infection by HIV occurs rarely, if at all, in the DRG of patients with HIV-SN. We thus hypothesize that the loss of DRG neurons and the sensory axonopathy seen in HIV-SN result from neurotoxicity by soluble mediators released by HIV-infected macrophages present in the DRG of these patients. These mediators include secreted viral proteins such as the HIV-1 envelope glycoprotein gp120, which we have shown recently is an extremely potent neurotoxin in rat embryonic DRG cultures. We postulate that gp120 released by H IV-infected macrophages in the DRG, causes both direct and indirect peripheral neurotoxicity via chemokine receptor ligation on neurons, macrophages and Schwann cells. Furthermore, as the severity of neuropathology does not always mirror the degree of pain that so dominates the symptomatology of HIV-SN, we suggest that gp120 may contribute to the pathogenesis of neuropathic pain by directly activating nociceptive neurons. This project aims to characterize gp120 neurotoxicity in human fetal DRG cultures, and elucidate the pathogenetic mechanisms leading to this neurotoxicity, so that therapeutic strategies can be devised. A major strength of our proposal is our use of human tissues to study a disease that only affects humans.