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变，通常表现为远端多神经病变（DSP）或抗逆转录病毒毒性神经病（ATN）。本研究利用猫免疫缺陷病毒（FIV）的多种感染性生物毒株和重组病毒，探讨慢病毒分子多样性在DSP发展中的作用。基于我们的前期研究和早期报道，我们假设通过表达不同env序列的特定FIV毒株感染周围神经，由于神经内的免疫激活以及伴随的全身免疫抑制，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，特异性抗逆转录病毒药物可以消除或加重DSP。为了研究病毒多样性对DSP的作用机制，我们建议使用一个定义良好的慢病毒感染体内模型，在该模型中，感染了FIV不同毒株或分子克隆的动物在神经行为学、电生理学、形态学和免疫学上进行评估，同时分析病毒异质性和周围神经和其他器官的负荷。为了支持这些体内研究，我们还将使用背根神经节来源的培养系统探索FIV环境介导的神经毒性的作用，使我们能够解剖单个细胞类型对DSP发病机制的相对贡献，包括巨噬细胞和雪旺细胞。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.