Peripheral neurotoxicity by the HIV-1 coat protein gp120

HIV-1 外壳蛋白 gp120 的周围神经毒性

• 批准号: 6998877
• 负责人: Ahmet Hoke
• 金额: $ 25.84万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6998877
• 关键词: AIDS /HIV neuropathy; HIV envelope protein gp120; Schwann cells; calcium flux; chemokine receptor; clinical research; enzyme linked immunosorbent assay; human tissue; macrophage; neurotoxicology; nociceptors; receptor binding; spinal ganglion; terminal nick end labeling; tissue /cell culture

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.

描述（由申请人提供）：与HIV相关的感觉神经病（HIV-SN）现在被认为是HIV感染最常见的神经系统并发症，对包括儿童和成人在内的艾滋病患者中有三分之一影响。到目前为止，很少关注探索这种非常痛苦的疾病的发病机理，目前没有有效的治疗方法。从病理上讲，HIV-SN的特征是背根神经节（DRG）感觉神经元，HIV感染的巨噬细胞浸润DRG以及“垂死的后背”感觉神经病。类似于HIV痴呆症的情况，HIV的神经元感染很少发生，如果有的话，在HIV-SN患者的DRG中很少发生。因此，我们假设DRG神经元的丧失和HIV-SN中的感觉轴突病因这些患者的DRG中存在的HIV感染巨噬细胞释放而引起的HIV-SN神经毒性引起的感觉。这些介质包括分泌的病毒蛋白，例如HIV-1包膜糖蛋白GP120，我们最近显示的是大鼠胚胎DRG培养物中极有效的神经毒素。我们假设HIV感染的巨噬细胞在DRG中释放的GP120会通过神经元，巨噬细胞和schwann细胞引起直接和间接周围神经毒性。此外，由于神经病理学的严重程度并不总是反映出主导HIV-SN症状的疼痛程度，因此我们建议GP120可能通过直接激活伤害性神经元来有助于神经性疼痛的发病机理。该项目旨在表征人类胎儿DRG培养物中的GP120神经毒性，并阐明导致这种神经毒性的致病机制，以便设计治疗策略。我们提出的主要优势是我们使用人体组织研究只会影响人类的疾病。