EcoHIV and neuropathic pain

项目摘要/摘要 慢性疼痛是人类免疫缺陷病毒1型(PLWH)携带者的一种主要健康状况，尽管 联合抗逆转录病毒疗法(ART)的使用。与其他人类免疫缺陷病毒(HIV)地区不同的是 研究(例如，艾滋病毒相关的神经认知障碍，疫苗)，慢性疼痛是一个研究不足的领域 尽管PLWH患者普遍存在疼痛，但缺乏有效的止痛治疗，而且研究不完全 对机制的理解。制定治疗策略和更好地了解艾滋病毒-- 相关的神经病理性疼痛机制由于缺乏合适的动物模型而受到阻碍。 PLWH中的慢性神经病理性疼痛。目前HIV相关神经病理性疼痛的小动物模型包括 急性注射单一的艾滋病毒病毒蛋白，如糖蛋白120(Gp120)。这种模式已经奏效了。 以确定对该病毒蛋白的疼痛反应及其作用机制。然而，除了gp120， 其他HIV病毒蛋白、HIV-1转录反式激活因子(TAT)和病毒蛋白R(VPR)可以产生疼痛。 因此，单一的艾滋病毒蛋白不太可能是导致艾滋病毒神经性疼痛和模仿艾滋病毒的唯一因素。 HIV持续存在并同时存在病毒蛋白的慢性疾病。 拟议的研究将检验这样一种假设，即感染EcoHIV的小鼠会出现神经病理性疼痛样症状。 有类似慢性神经病理性疼痛的PLWH的行为和病理改变的情况。一个 行为学、药理学、分子生物学、生物化学和组织病理学的多学科方法将 检验这一假设。目的1.我们将进行全面的研究，以确定EcoHIV中神经病理性疼痛的特征。 受感染的小鼠。我们将使用一系列对感觉性和自发性/持续性疼痛的行为评估。 分析临床上用于诊断HIV相关周围神经病的标志物(例如， 表皮内神经纤维密度)将用于验证EcoHIV相关神经病理性疼痛模型。我们会 还要分析神经炎症，这是诱导和维持慢性疼痛的关键因素。 拟议的研究将对艾滋病毒和疼痛领域产生重大影响，因为它提供了一种小动物 研究HIV相关神经病理性疼痛的模型，这一直是缺乏的。与EcoHIV相关的特征 神经病理性疼痛模型将推动当前关于艾滋病毒背景下疼痛的研究，为以下方面奠定基础 迫切需要的研究。

PROJECT SUMMARY/ABSTRACT Chronic pain is a major health condition in people living with Human Immunodeficiency Virus-1 (PLWH) despite the use of combined antiretroviral therapy (ART). Unlike other human immunodeficiency virus (HIV) areas of research (e.g., HIV-associated neurocognitive disorder, vaccine), chronic pain is an understudied area of research despite the prevalence of pain in PLWH, lack of effective analgesic therapy, and incomplete understanding of mechanisms. The development of therapeutic strategies and a better understanding of HIV- related neuropathic pain mechanisms have been hampered by the lack of a suitable animal model that mimics chronic neuropathic pain in PLWH. The current small animal model for HIV-related neuropathic pain consists of the acute administration of a single HIV viral protein, such as glycoprotein 120 (gp120). This model has served to determine the pain response to this viral protein and its mechanism of action. However, in addition to gp120, other HIV viral proteins, HIV-1 transactivator of transcription (Tat), and Viral protein R (Vpr) can produce pain. Therefore, a single HIV protein is unlikely to be the only contributor to HIV-neuropathic pain and mimics the HIV chronic condition where there is a continuous presence of HIV and a simultaneous presence of viral proteins. The proposed studies will test the hypothesis that EcoHIV-infected mice develop a neuropathic pain-like condition with behavioral and pathological changes that mimic PLWH with chronic neuropathic pain. A multidisciplinary approach of behavior, pharmacology, molecular biology, biochemistry, and histopathology will test this hypothesis. Aim 1. We will perform comprehensive studies to characterize neuropathic pain in EcoHIV- infected mice. We will use a battery of behavioral assessments of sensory and spontaneous/ongoing pain. Analyzing markers clinically used for the diagnosis of HIV-associated peripheral neuropathy (e.g., decrease in intraepidermal nerve fiber density) will serve to validate the EcoHIV-associated neuropathic pain model. We will also analyze neuroinflammation, a key player in the induction and maintenance of chronic pain. The proposed studies will have a significant impact on the fields of HIV and pain by providing a small animal model to study HIV-related neuropathic pain, which has been lacking. Characterization of the EcoHIV-related neuropathic pain model will advance current research on pain in the context of HIV by laying the groundwork for urgently and critically needed studies.