LENTIVIRUS-INDUCED NEUROPATHY: VIRAL DIVERSITY AND HOST*

描述（由申请人提供）：目前在发达国家观察到的HIV/AIDS的主要神经系统并发症是周围神经病，通常表现为远端多发性神经病（DSP）或抗逆转录病毒毒性神经病（ATN）。本提案探讨了慢病毒分子多样性的作用，DSP的发展，使用多种传染性生物株和重组病毒的猫免疫缺陷病毒（FIV）。基于我们的初步研究和早期报道，我们假设，通过选择表达不同env序列的FIV毒株感染外周神经，由于神经内的免疫激活以及伴随的全身免疫抑制而导致DSP的发展。此外，神经内的病毒异质性和载量决定了DSP的严重程度，可以用特定的抗逆转录病毒药物消除或加重。为了研究病毒多样性导致DSP的机制，我们建议使用定义明确的慢病毒感染体内模型，在该模型中，对感染不同株系或FIV分子克隆的动物进行神经行为学、电生理学、形态学和免疫学评估，并结合外周神经和其他器官中的病毒异质性和负荷分析。为了支持这些体内研究，我们还将使用背根神经节衍生的培养系统探索FIV env介导的神经毒性的作用，使我们能够剖析单个细胞类型对DSP发病机制的相对贡献，包括巨噬细胞和许旺细胞。从这些研究中，我们期望从慢病毒诱导的神经毒力和致病性宿主反应方面深入了解这种常见的神经系统并发症。

DESCRIPTION (provided by applicant): The principal neurological complication of HIV/AIDS observed in the developed world is currently peripheral neuropathy, usually manifested as distal polyneuropathy (DSP) or antiretroviral toxic neuropathy (ATN). This proposal examines the role of lentivirus molecular diversity in relation to the development of DSP, using multiple infectious biological strains and recombinant viruses of feline immunodeficiency virus (FIV). Based on our preliminary studies and earlier reports, we hypothesize that infection of peripheral nerves by select FIV strains, expressing different env sequence contributes to the development of DSP due to immune activation within the nerve together with concomitant systemic immune suppression. Moreover, viral heterogeneity and load within the nerve determine the severity of DSP, which can be abrogated or exacerbated with specific antiretroviral drugs. To investigate the mechanisms by which viral diversity contributes to DSP, we propose to use a well defined in vivo model of lentivirus infection in which animals infected with different strains or molecular clones of FIV are assessed neurobehaviorally, electrophysiologically, morphologically and immunologically in conjunction with analyses of viral heterogeneity and load in peripheral nerve and other organs. To support these in vivo studies, we will also explore the role of FIV env-mediated neurotoxicity using a dorsal root ganglia-derived culture system, allowing us to dissect the relative contributions of individual cell types to the pathogenesis of DSP including macrophages and Schwann cells. From these studies, we expect to gain insights into this common neurological complication in terms of lentivirus-induced neurovirulence and pathogenic host responses.