HIV Tat-associated Sensory Neuropathy and the Contribution of Toll-like Receptor Pathway

摘要 周围神经疾病是与艾滋病毒有关的最常见的神经系统并发症，其中 HIV感觉神经病(HIV-SN)是最常见的形式，影响到近一半的艾滋病毒/艾滋病患者 患病率为1.2-69.4%。HIV-SN经常表现为难以控制的疼痛，并经常 诊断不足和/或治疗不足，然而，患病率的巨大差异不允许检测到 暴露于HAART的个体与未暴露于HAART的个体之间的患病率有显著差异。的确有 没有FDA批准的针对HIV-SN的特定治疗方法。TAT，转录反式激活因子，一种调节蛋白 在HIV感染后表达的第一批蛋白质中，是HIV转录的关键激活因子，可以影响 HIV感染的细胞和未感染的邻近细胞都通过感染细胞的分泌物进行分泌。虽然是人类 最近使用两种多西环素诱导的HIV-1Tat转基因模型进行的动物实验缺乏研究。 来自我们实验室和其他实验室的(ITAT)小鼠提供了令人信服的证据，证明艾滋病毒TAT有助于发育 是HIV-SN的。因此，在这项建议中，我们将进一步研究与TAT相关的潜在机制 序列号。我们的初步研究确定了TAT对Toll样受体(TLR)信号通路的潜在调节作用。 考虑到广泛接受的TLR通路参与神经病理性疼痛，令人惊讶的是缺乏研究 为了探讨TLR通路在HIV-SN中的作用，本研究将重点研究TAT相关SN中的TLR通路。 我们将利用生物信息学工具来识别FDA批准的药物，而不会有重大的相互作用 现有的抗逆转录病毒药物可能逆转TAT诱导的TLR途径的变化，然后 在体内测试其治疗TAT相关性SN的有效性。总之，我们假设TLR信号 途径参与了HIV-TAT相关SN的发展，有可能识别潜在的 通过生物信息学和临床前模型检查现有药物治疗HIV-SN 接近。这将通过两个具体目标进行测试。目标1将决定Tollip(一个关键)的贡献 TLR途径的调节者)调节HIV TAT相关SN中的TLR途径 动物模型结合行为和生理测试。AIM 2将确定潜在的药物 通过生物信息学和临床前模型相结合的方法靶向TLR途径的HIV-SN。如果 如果成功，我们将填补关于与TAT相关的SN和TLRs在HIV-SN中的作用的知识空白。我们的 全面的联合药物发现战略将有助于确定治疗艾滋病毒-SN的潜在药物，这些药物可以 在临床评估之前，进一步在其他动物模型中进行测试。在整个过程中，我们将优先考虑 候选药物是机械可靠的，并且可能很容易为所有患者所用。

Summary Peripheral neuropathies are the most frequent neurological complications associated with HIV, within which HIV sensory neuropathy (HIV-SN) is the most common form, affecting nearly half of HIV/AIDS patients with the prevalence ranging from 1.2 – 69.4%. HIV-SN frequently manifests with hard-to-manage pain and is often under-diagnosed and/or under-treated, yet, the large variation in prevalence does not allow for detection of significant differences in prevalence between HAART-exposed vs. HAART-non-exposed individuals. There is no specific FDA-approved treatment for HIV-SN. Tat, trans-activator of transcription, a regulatory protein among the first proteins expressed following HIV infection, is a key activator of HIV transcription and can affect both HIV infected cells and non-infected neighboring cells via its secretion by infected cells. Although human studies are lacking, recent animal studies using two models of doxycycline-inducible HIV-1 Tat transgenic (iTat) mice from our lab and others provided convincing evidence that HIV Tat contributes to the development of HIV-SN. Therefore, in this proposal, we will further investigate the underlying mechanisms of Tat-associated SN. Our preliminary study identified potential regulation of Tat of Toll-like receptor (TLR) signaling pathway. Given the widely accepted involvement of TLR pathway in neuropathic pain and surprising lack of studies exploring the role of TLR pathway in HIV-SN, we will focus on TLR pathway in Tat-associated SN in this study. We will take advantage of bioinformatic tools to identify FDA-approved drugs without significant interactions with existing antiretroviral drugs that could potentially reverse Tat-induced changes in TLR pathway, and then test their effectiveness in treating Tat-associated SN in vivo. Altogether, we hypothesize that TLR signaling pathway is involved in the development of HIV-Tat-associated SN and it is possible to identify potential treatment for HIV-SN by examining existing drugs via a combined bioinformatics and pre-clinical model approach. This will be tested through 2 Specific Aims. Aim 1 will determine the contribution of Tollip (a key regulator of TLR pathway)-regulated TLR pathways in HIV Tat-associated SN using genetically modified animal models in combination with behavioral and physiological tests. Aim 2 will identify potential drugs for HIV-SN by targeting TLR pathway via a combined bioinformatics and pre-clinical model approach. If successful, we will fill in the knowledge gaps regarding Tat-associated SN and TLRs’ role in HIV-SN. Our comprehensive combination drug discovery strategy will help identify potential drugs for HIV-SN, which can be further tested in other animal models before clinical assessment. Throughout the process, we will prioritize drug candidates that are mechanistically-sound, and potentially easily accessible to all patients.