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

描述（由申请人提供）：远端对称多神经病变（DSP）是人类免疫缺陷病毒（HIV）感染相关的周围神经病变最常见的形式，通常与疼痛相关，然而它经常被诊断和/或治疗不足。不幸的是，在当前广泛的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，可用的动物模型很少。先前的研究表明，C57BL/6小鼠感染LP-BM5（一种小鼠逆转录病毒分离物）后，会出现与人类感染HIV相似的严重获得性免疫缺陷综合征，因此称为小鼠艾滋病（MAIDS）。LP-BM5感染还会在C57BL/6小鼠中诱发中枢神经系统脑病和认知缺陷，这可以通过抗逆转录病毒药物azidothymidine治疗来预防。我们的初步实验表明，LP-BM5诱导后肢明显的机械过敏和足垫皮肤周围神经纤维的丧失，周围神经病变的迹象，随着女佣人的发展，提示LP-BM5感染可能是HIV/AIDS相关疼痛周围神经病变的潜在啮齿动物模型。本研究首次尝试表征lp - bm5诱导的C57BL/6小鼠周围神经病变，并探讨lp - bm5诱导的神经病变机制。我们假设外周LP-BM5病毒感染导致易感C57BL/6小鼠后肢机械过敏和足垫表皮内神经纤维（IENF）密度降低的疼痛性周围神经病变，脊髓小胶质LP-BM5感染及其直接或间接诱导小胶质CD40上调有助于LP-BM5诱导的周围神经病变。中心假设将通过三个具体目标进行检验：1)表征lp - bm5诱导的周围神经病变发展的时间进程；2)确定LP-BM5在腰椎的特异性细胞靶点；3)确定脊髓小胶质细胞CD40在lp - bm5诱导的周围神经病变中的作用。已知CD154 (CD40L)-CD40相互作用在maid特征的发展中至关重要。此外，CD40信号和CNS小胶质细胞在HIV脑炎和周围神经损伤性神经病的发病机制中都是至关重要的。评估小胶质细胞CD40的作用将进一步提供lp - bm5诱导的周围神经病变的潜在机制。这项研究的长期目标是进一步了解逆转录病毒感染引起的神经病变，从而更好地理解和更有效地治疗HIV感染相关的疼痛周围神经病变。

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.