Peripheral neurotoxicity by the HIV-1 coat protein gp120

描述(申请人提供)：艾滋病毒相关感觉神经病(HIV-SN)现在被认为是艾滋病毒感染最常见的神经系统并发症，症状影响三分之一的艾滋病患者，包括儿童和成人。到目前为止，很少有人致力于探索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。从病理学上讲，HIV-SN的特征是背根神经节(DRG)感觉神经元的丢失，HIV感染的巨噬细胞对DRG的渗透，以及一种‘垂死性’感觉神经病。与HIV痴呆症的情况类似，HIV-SN患者的DRG中很少发生HIV神经元感染，如果有的话。因此，我们假设，在HIV-SN中看到的DRG神经元的丢失和感觉性轴索病变是由这些患者的DRG中存在的HIV感染的巨噬细胞释放的可溶性介质引起的神经毒性所致。这些介体包括分泌的病毒蛋白，如HIV-1包膜糖蛋白gp120，我们最近证明它是一种在大鼠胚胎DRG培养中非常有效的神经毒素。我们推测，HIV感染的巨噬细胞释放的gp120通过与神经元、巨噬细胞和雪旺细胞上的趋化因子受体连接而引起直接和间接的外周神经毒性。此外，由于神经病理的严重程度并不总是反映支配HIV-SN症状的疼痛程度，我们认为gp120可能通过直接激活伤害性神经元而参与神经病理性疼痛的发病。本项目旨在研究gp120对培养的人胎儿背根节的神经毒性，并阐明导致这种神经毒性的致病机制，以便制定治疗策略。我们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.