Mechanisms of HIV-Induced PNS Disease: The SIV Macaque Model

HIV 引起的 PNS 疾病的机制：SIV 猕猴模型

• 批准号: 7437378
• 负责人: JOSEPH L MANKOWSKI
• 金额: $ 60.34万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-13 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7437378
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; Affect; Animal Model; Animals; Anti-Retroviral Agents; Axon; Bilateral; C Fiber; Central Nervous System Diseases; Complication; Disease; Distal; Encephalitis; Fiber; Fostering; Goals; HIV; HIV neuropathy; HIV-1; High Prevalence; Highly Active Antiretroviral Therapy; Incidence; Individual; Infection; Inflammation; Injury; Laboratories; Leg; Location; MAPK14 gene; Macaca; Measures; Modeling; Molecular; Nerve; Nerve Fibers; Neurologic; Neurons; Neuropathy; Numbers; Pain; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Polyneuropathy; Primates; Production; Property; Proteins; Quality of life; Reporting; SIV; Sensory; Sensory Ganglia; Skin; Sodium Channel; Spinal Ganglia; Staging; Therapeutic; Time; Viral; Virus; Virus Replication; base; day; drug development; foot; foot sole; macrophage; neuron loss; neuronal cell body; neurotoxic; novel; novel therapeutics; p38 MAPK Signaling Pathway; sensory neuropathy; somatosensory; sural nerve

DESCRIPTION (provided by applicant): Peripheral neuropathy is the most common neurological complication associated with HIV-1 infection, affecting over one-third of HIV-infected individuals with AIDS. In addition, studies have found a high prevalence of HIV sensory neuropathy in HIV-infected patients receiving highly active antiretroviral therapy. Although HIV-induced damage to the peripheral nervous system is a frequent and debilitating consequence of infection, its pathogenesis is incompletely understood. To study this disease, we established an SIV/macaque model in which over 90 percent of animals develop PNS changes closely resembling those seen in HIV-infected individuals with distal sensory neuropathy, including inflammation of the dorsal root ganglia with abundant replication of SIV in macrophages and neuronal loss, sural nerve inflammation, and reduction in the number of epidermal nerve fibers in the feet. This constitutes the first primate model of HIV-induced peripheral neuropathy. Our goal is to use this model to dissect the pathogenesis and the underlying molecular basis of HIV-induced PNS disease. Our hypothesis is that HIV first replicates in macrophages within the DRG in the PNS, inducing a cascade of viral and macrophage-produced neurotoxic products, which activate p38 MAPK signaling pathways in somatosensory neurons that trigger sodium channel dysregulation. To address this hypothesis, we have proposed three Aims: Aim 1 is to determine whether SIV-induced PNS disease is initiated by replication of gangliotropic viruses that trigger production of neurotoxic viral and macrophage gene products in the DRG of SIV- infected macaques and to determine whether neurovirulent viruses remain latent in the DRG when no active virus replication is detected in DRG. Aim 2 is to determine the order in which components of the pain pathway, including DRG, sensory fibers in peripheral nerve, and epidermal nerve fibers are damaged in DSP. Aim 3 is to determine whether a) SIV-induced PNS disease is associated with altered conductive properties of unmyelinated C fibers and alterations in expression levels and distribution of sodium channels in DRG neurons, and b) to determine whether active replication of SIV in DRG macrophages induces activation of p38 in DRG neurons thereby modulating the expression and location of sodium channels in DRG neurons. The goal of these comprehensive, integrated studies of HIV sensory neuropathy in our novel SIV primate model is to advance the understanding of HIV-SN pathogenesis to foster new therapeutic approaches.

描述（由申请人提供）：周围神经病变是与HIV-1感染相关的最常见的神经系统并发症，影响超过三分之一的HIV感染者。此外，研究发现，在接受高效抗逆转录病毒治疗的艾滋病毒感染患者中，艾滋病毒感觉神经病的发病率很高。虽然HIV引起的周围神经系统损伤是感染的常见和衰弱的后果，但其发病机制尚未完全了解。为了研究这种疾病，我们建立了一个SIV/猕猴模型，其中超过90%的动物发生PNS变化，与HIV感染个体的远端感觉神经病变非常相似，包括背根神经节炎症，巨噬细胞中大量复制SIV和神经元丢失，腓肠神经炎症和足部表皮神经纤维数量减少。这构成了第一个HIV诱导的周围神经病变的灵长类动物模型。我们的目标是使用这个模型来剖析HIV诱导的PNS疾病的发病机制和潜在的分子基础。我们的假设是，HIV首先在PNS的DRG内的巨噬细胞中复制，诱导病毒和巨噬细胞产生的神经毒性产物的级联反应，其激活躯体感觉神经元中的p38 MAPK信号通路，从而触发钠通道失调。为了解决这一假设，我们提出了三个目的：目的1是确定SIV诱导的PNS疾病是否是由在SIV感染的猕猴的DRG中触发神经毒性病毒和巨噬细胞基因产物的产生的亲神经节病毒的复制引发的，并且确定当在DRG中没有检测到活性病毒复制时，神经毒性病毒是否在DRG中保持潜伏。目的2是确定在DSP中疼痛通路的组成部分，包括DRG、周围神经中的感觉纤维和表皮神经纤维的损伤顺序。目的3是确定a）SIV诱导的PNS疾病是否与无髓鞘C纤维的传导特性改变以及DRG神经元中钠通道的表达水平和分布的改变相关，和B）确定SIV在DRG巨噬细胞中的主动复制是否诱导DRG神经元中p38的活化，从而调节DRG神经元中钠通道的表达和位置。在我们的新型SIV灵长类动物模型中对HIV感觉神经病变进行这些全面综合研究的目的是促进对HIV-SN发病机制的理解，以促进新的治疗方法。