Murine AIDS (LP-BM5) viral infection induced peripheral neuropathy - Role of CNS

描述(申请人提供)：远端对称性多发性神经病(DSP)是人类免疫缺陷病毒(HIV)感染相关的最常见的周围神经病，经常与疼痛有关，但通常被低估和/或治疗不足。不幸的是，在目前广泛的HIV/AIDS(获得性免疫缺陷综合征)研究中，DSP是一个研究不足的领域，几乎没有可用的动物模型。此前已有研究表明，感染Lp-BM5(一种小鼠逆转录病毒株)的C57BL/6小鼠会出现一种严重的获得性免疫缺陷综合征，与感染艾滋病毒的人类相似，因此被称为小鼠艾滋病(MAIDS)。Lp-BM5感染也会导致C57BL/6小鼠的中枢神经系统脑病和认知障碍，这些都可以通过抗逆转录病毒药物齐多夫定来预防。我们的初步实验结果表明，Lp-BM5可引起显著的后肢机械超敏反应和足垫皮肤周围神经纤维的丢失，伴随着女佣的发育，提示Lp-BM5感染可能是一种潜在的HIV/AIDS相关性痛性周围神经病的啮齿动物模型。本研究首次对Lp-BM5诱导的C57BL/6小鼠周围神经病变进行了定性研究，并探讨了Lp-BM5诱导周围神经病变的机制。我们推测，外周Lp-BM5病毒感染导致痛性周围神经病变，表现为后肢机械过敏和足垫表皮内神经纤维密度降低，脊髓小胶质细胞Lp-BM5感染及其直接或间接诱导小胶质细胞CD40上调是Lp-BM5诱导的周围神经病变的原因。中心假说将通过三个具体目标得到验证：1)表征Lp-BM5诱导的周围神经病的发展过程；2)确定Lp-BM5在腰髓中的特异性细胞靶点；3)确定脊髓小胶质细胞CD40在Lp-BM5诱导的周围神经病中的作用。CD154(CD40L)-CD40的相互作用在女仆的发育过程中起着至关重要的作用。此外，CD40信号和中枢神经系统小胶质细胞在HIV脑炎和周围神经损伤所致神经病的发病机制中都起着关键作用。评估小胶质细胞CD40的作用将进一步提供参与LP-BM5诱导的周围神经病变的潜在机制。这项拟议研究的长期目标是提供关于逆转录病毒感染引起的神经病的进一步知识，从而更好地理解和更有效地治疗艾滋病毒感染相关的痛性周围神经病。 与公共卫生的相关性：据估计，截至2007年底，全世界有3300万人患有艾滋病毒/获得性免疫缺陷综合征(艾滋病)(2007年联合国艾滋病疫情最新报告)，因此，目前正更多地关注艾滋病毒感染相关并发症的治疗。摘要痛性远端对称性多发性神经病(DSP)是HIV感染相关性周围神经病变中最常见的一种，由于缺乏有效的动物模型，常被漏诊和/或治疗。目前的研究对建立与人类DSP相关的HIV感染啮齿动物模型具有巨大的潜力，并可能导致更有效的治疗。

DESCRIPTION (provided by applicant): Distal symmetrical polyneuropathy (DSP) is the most common form of human immunodeficiency virus (HIV) infection-associated peripheral neuropathy and is frequently associated with pain, however it is often under-diagnosed and/or under-treated. Unfortunately, amongst the extensive current HIV/AIDS (acquired immunodeficiency syndrome) research, DSP is an understudied area with few animal models available. It has been previously shown that C57BL/6 mice infected with LP-BM5, a murine retroviral isolate, develop a severe acquired immunodeficiency syndrome similar to humans infected with HIV, hence the term murine AIDS (MAIDS). LP-BM5 infection also induces CNS encephalopathy and cognitive deficits in C57BL/6 mice that are prevented by treatment with the anti-retroviral agent azidothymidine. Our preliminary experiment shows that LP-BM5 induced significant hind limb mechanical hypersensitivity and loss of peripheral nerve fibers in the foot pad skins, signs of peripheral neuropathy, along with the development of MAIDS, suggesting that LP-BM5 infection could be a potential rodent model of HIV/AIDS associated painful peripheral neuropathy. The current proposal is the first attempt to characterize LP-BM5-induced peripheral neuropathy in C57BL/6 mice and investigate the mechanisms in LP-BM5-induced neuropathy. We hypothesize that peripheral LP-BM5 viral infection leads to a painful peripheral neuropathy, presented as hind limb mechanical hypersensitivity and reduced foot pad intraepidermal nerve fiber (IENF) density in susceptible C57BL/6 mice and that spinal cord microglial LP-BM5 infection and its direct or indirect induction of microglial CD40 up- regulation contribute to LP-BM5-induced peripheral neuropathy. The central hypothesis will be tested through three specific aims: 1) Characterize the time course of the development of LP-BM5-induced peripheral neuropathy; 2) Identify the specific cellular target of LP-BM5 in the lumbar spinal cord; and 3) Determine the role of spinal cord microglial CD40 in LP-BM5-induced peripheral neuropathy. CD154 (CD40L)-CD40 interaction is known to be critical in the development of the features of MAIDS. Also both CD40 signaling and CNS microglia are critical in the pathogenesis of HIV encephalitis as well as peripheral nerve injury-induced neuropathy. Assessing the role of microglial CD40 will further provide underlying mechanisms involved in the LP-BM5-induced peripheral neuropathy. The long-term goal of the proposed study is to provide further knowledge on retroviral infection-induced neuropathy that could lead to a better understanding of, and more effective treatments for, HIV infection-associated painful peripheral neuropathy. PUBLIC HEALTH RELEVANCE: It is estimated that 33 million people worldwide were living with HIV/acquired immunodeficiency syndrome (AIDS) at the end of 2007 (The 2007 United Nations AIDS epidemic update reports), and as such, greater attention is being focused on the treatment of the numerous HIV infection-related complications. As the most common form of HIV infection-associated peripheral neuropathy, painful distal symmetrical polyneuropathy (DSP) is often under-diagnosed and/or under-treated partially due to a lack of available animal models. The current study carries great potential for establishing a rodent model of HIV infection associated DSP in humans and may lead to more effective treatments.