LENTIVIRUS-INDUCED NEUROPATHY: VIRAL DIVERSITY AND HOST*

描述(申请人提供)：目前在发达国家观察到的艾滋病毒/艾滋病的主要神经并发症是周围神经病，通常表现为远端多神经病(DSP)或抗逆转录病毒中毒性神经病(ATN)。这项建议利用多种感染性生物毒株和猫免疫缺陷病毒(FIV)的重组病毒，研究了慢病毒分子多样性在DSP发展中的作用。根据我们的初步研究和早期报道，我们推测，表达不同env序列的FIV株感染周围神经可能是由于神经内的免疫激活和伴随的全身免疫抑制而导致的。此外，神经内病毒的异质性和负载决定了DSP的严重程度，这种严重程度可以用特定的抗逆转录病毒药物来消除或加重。为了研究病毒多样性对DSP的影响机制，我们建议使用一个定义良好的慢病毒体内感染模型，在该模型中，对感染不同毒株或分子克隆的FIV的动物进行神经行为、电生理、形态和免疫学评估，并结合周围神经和其他器官中病毒的异质性和载量的分析。为了支持这些体内研究，我们还将使用背根节来源的培养系统来探索FIV env介导的神经毒性的作用，使我们能够剖析包括巨噬细胞和雪旺细胞在内的单个细胞类型在DSP发病中的相对贡献。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对这种常见的神经系统并发症有深入的了解。

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.