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

总结 周围神经病变是与HIV相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，影响近一半的HIV/AIDS患者， 患病率为1.2 - 69.4%。HIV-SN经常表现为难以控制的疼痛， 诊断不足和/或治疗不足，然而，患病率的巨大变化不允许检测 HAART暴露与HAART非暴露个体之间的患病率存在显著差异。有 没有FDA批准的针对HIV-SN的特定治疗。达特，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转录的关键激活剂， HIV感染的细胞和未感染的邻近细胞通过其被感染的细胞分泌。虽然人类 缺乏研究，最近的动物研究使用两种模型的多西环素诱导的HIV-1达特转基因 来自我们实验室和其他实验室的i达特小鼠提供了令人信服的证据，证明HIV达特有助于发展 HIV-SN的。因此，在本提案中，我们将进一步研究Tat相关的潜在机制。 SN.我们的初步研究发现达特对Toll样受体（TLR）信号通路具有潜在的调节作用。 鉴于TLR途径广泛接受参与神经性疼痛并且令人惊讶地缺乏研究 为探讨TLR通路在HIV-SN中的作用，本研究将重点关注TLR通路在Tat相关SN中的作用。 我们将利用生物信息学工具来识别FDA批准的药物， 与现有的抗逆转录病毒药物，可能会逆转Tat诱导的TLR途径的变化， 测试它们在体内治疗Tat相关SN的有效性。总之，我们假设TLR信号传导 途径参与了HIV-Tat相关SN的发展，并且有可能确定潜在的 通过联合生物信息学和临床前模型检查现有药物治疗HIV-SN approach.这将通过两个具体目标进行测试。目标1将决定Tollip的贡献（一个关键 TLR途径的调节子）-使用基因修饰的HIV Tat相关SN中调节的TLR途径 结合行为和生理测试的动物模型。目标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通路的HIV-SN。如果 如果成功，我们将填补有关Tat相关SN和TLR在HIV-SN中作用的知识空白。我们 全面的联合药物发现策略将有助于确定治疗HIV-SN的潜在药物， 在临床评估之前在其他动物模型中进一步测试。在整个过程中，我们将优先考虑 候选药物是机械上健全的，并且可能容易被所有患者获得。

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.