HIV and NRTI's-induced painful pathogenic mechanisms and gene therapy

描述（由申请人提供）：HIV患者通常会出现疼痛的神经病变，这种病变会因高活性抗逆转录病毒治疗（HAART）而加重。最近通过将gp120应用于坐骨神经并全身给予核苷类逆转录酶抑制剂（NRTIs）而建立的动物模型的发展，使得研究HIV/HAART神经性疼痛的发病机制成为可能。我们和其他人已经描述了神经性疼痛中背根神经节（DRG）肿瘤坏死因子（TNFa）的增加和脊髓小胶质细胞的激活。在其他神经性疼痛模型中，已经描述了背角活性氧（ROS）的增加和gaba能张力的降低。背角抑制和促进冲动之间的平衡被破坏是疼痛超敏反应的主要机制。提出的研究将验证以下假设：HIV/HAART神经病变的疼痛源于促炎细胞因子的产生，促炎细胞因子导致ROS释放，导致脊髓背角gaba能张力降低。我们拟采用HIV/HAART神经病变模型进行一系列实验，目的是：1)确定HIV相关疼痛时DRG和脊髓中TNFa、ROS、谷氨酸脱羧酶（GAD）和GABA的变化；2)严格检验TNFa升高与ROS之间的关系；3)研究ROS与gaba能张力的关系；4)确定单纯疱疹病毒载体介导的基因转移增加抗炎细胞因子和抑制DRG的氨基酸是否可以减轻hiv相关疼痛及其神经化学机制。这些研究结果将为HIV/AIDS患者神经性疼痛的发病机制提供重要的见解，并可能为一种新的治疗方法提供临床前证据。

DESCRIPTION (provided by applicant): Patients with HIV often develop a painful neuropathy that is exacerbated by treatment with highly active anti-retroviral therapy (HAART). The recent development of animal models, created by application of gp120 to the sciatic nerve along with systemic administration of nucleoside reverse transcriptase inhibitors (NRTIs), have allowed studies of the pathogenesis of HIV/HAART neuropathic pain. We and others have described an increase in tumor necrosis factor (TNFa) in dorsal root ganglia (DRG) and activation of spinal microglia in the neuropathic pain. In other models of neuropathic pain, increases in reactive oxygen species (ROS) and decreases in GABAergic tone in the dorsal horn have been described. A disturbed balance between inhibitory and facilitatory impulses in the dorsal horn is the main mechanisms for pain hypersensitivity. The studies proposed will test the hypothesis that: pain in HIV/HAART neuropathy results from the production of proinflammatory cytokines that result in the release of ROS leading to a reduction in GABAergic tone in the dorsal horn of spinal cord. We propose a series of experiments with models of HIV/HAART neuropathy to: 1) define the changes of TNFa, ROS, glutamic acid decarboxylase (GAD) and GABA in DRG and spinal cord in HIV-associated pain; 2) critically test the relationship between elevations in TNFa and ROS; 3) examine the relationship between ROS and GABAergic tone; and 4) determine whether HIV-associated pain can be reduced by herpes simplex virus vector-mediated gene transfer to increase anti-inflammatory cytokine and inhibitory amino acid to DRG and their neurochemical mechanisms. The results of these studies will provide important insights into the pathogenesis of neuropathic pain in patients with HIV/AIDS, and may provide preclinical evidence for a novel therapy. PUBLIC HEALTH RELEVANCE: One of the most debilitating neurological complications of HIV infection is painful neuropathy associated with nucleoside reverse transcriptase inhibitors (NRTIs). This study may help us understand the mechanism of pain better so that we can find a novel way to reduce pain.