Wnt5a, HIV外周神经病的关键通路及治疗靶点

Human immunodeficiency virus (HIV) peripheral sensory neuropathy (hHIV-SN) has been recognized as one of the common neurologic manifestations associated with most stages of HIV. Neuropathy cause pain in patients makes HIV associated pain as the secondary disease in which pain medical bill to treat is only lower than cancer pain. Currently, there is no effective, FDA-approved medicine for it. Major treatments provide only symptomatic control and pain management. To develop disease-specific and mechanism-based therapeutics for HIV-SN, it is essential to elucidate the underlying pathogenic mechanism. Although we know that both HIV-1 virus and combination anti-retroviral therapy (cART) can cause hHIV-SN, the specific pathogenic processes in sensory neurons remain elusive. .In our preliminary experiment, we found HIV-1 gp120 protein cause neuropathic pain, pain related molecular changes, synaptic pathologic changes, and most importantly the mice developed neuropathy (mHIV-SN) which was critically similar to HIV patients with pain syndrome. In this mouse, we also found that Wnt5a was aberrant up-regulated in the spinal dorsal horn (SCDH). Wnt5a is physiologically which only located in neurons and the role of Wnt5a in neuronal development and synaptic plasticity has been well elucidated. However, the role of Wnt5a in neuro-inflammation arose remained to be elucidated. Applicant’s previous working lab was one of the three major Wnt and pain research labs. To continue search Wnt5a role in HIV associate pain and SN, we plan to use this HIV-1 gp120 pain/SN mouse to investigate: ①The axon pathology of mHIV-SN, and Wnt5a activation pattern in DRG and related signaling mechanism and down-stream effectiveness. ② Base on the full observation of the neuropathic pain, axon pathology and degeneration and neuro-inflammation in mHIV-SN , we will analysis the pattern of axon pathology in hHIV-SN and explore human specific neuropathy mechanism. ③Determine the effectiveness of Wnt5a antagonist, Box5 in preventing or reversing mHIV-SN, optimizing different doses, usage and confirm the possibility that it might be serve as an adjuvant of cART.

HIV感染并发的外周感觉神经病（hHIV- SN）是引起疼痛的主要原因。现对其在感觉神经细胞（DRG）和轴突的的病变机制还缺乏深入了解，因此制约了“对因”治疗药物的研发，至今没有FDA批准的专用治疗药。Wnt5a蛋白是在神经发育和突轴可塑性上具有多种活性的蛋白。我们在预试验中发现Wnt5a在HIV-1 gp120蛋白引起的小鼠HIV疼痛模型的脊髓后角细胞内高表达。本研究目的：①研究Wnt5a在DRG细胞被激活的规律、机制及下游效应，Wnt5a异常高表达与小鼠mHIV-SN，人hHIV-SN轴突病变的关系。②对收集的hHIV-SN病人皮肤样品进行轴突病变分析，证实mHIV-SN与hHIV-SN的相似性，获得我国hHIV-SN外周神经病的特征和发病规律，与抗HIV治疗的关系。 ③进行Wnt5a拮抗剂、Box5减缓或逆转mHIV-SN治疗方案的优化试验，找到基于分子机制的hHIV-SN治疗手段。

人类免疫缺陷病毒（HIV）感染在世界范围内对人类健康造成了极大的危害。据WHO的统计数据，截至2019年全球共有3800万人感染HIV，死亡人数为69万。HIV感染严重影响着患者的健康状况。联合国AIDS(acquired immune deficiency syndrome) 的统计显示我国估计HIV感染人数约754万，但实际感染率应高于此数。HIV相关外周神经性病变（HIV-associated sensory neuropathy, HIV-SN）是HIV感染常见的慢性并发症。研究显示，临床上约57%的HIV感染者存在外周感觉神经病变，忍受感觉神经病变引起的疼痛的折磨；而尸检证实90%-100%的病人并发外周神经病，并增加患者死亡率。同时，随着HIV得到有效控制，病人生命延长， HIV-SN发生的机会增加，且伴随终生。HIV-SN可单纯由HIV感染引起,而用于HIV抗逆转录病毒疗法（combination antiretroviraltherapy, cART） 的核苷酸逆转录酶抑制剂也是HIV-SN的另一大诱因，这进一步加重了HIV引发的HIV-SN。病毒性HIV-SN和药源性HIV-SN 的发病机理有所不同，但其主要临床表现都是各种疼痛，在临床上难以区分开来。HIV感染可引起各种疼痛，包括内脏痛、关节痛、头痛以及全身皮肤的痛觉过敏等，用于控制其疼痛的医疗费用仅次于癌症痛而居第二。对于HIV-SN所引起的疼痛的治疗，目前除了对症止痛之外，无FDA批准的“对因”治疗药物。究其原因，主要是因为对HIV感染或药物治疗引起的伤害性感受器的病理变化机制缺乏透彻了解，严重阻碍了基于病因的治疗药物的研发。本课题全面而系统地探索了Wnt信号通路在HIV包膜蛋白gp120及HIV抗逆转录病毒疗法介导的神经病理性疼痛发生机制中的作用，探讨了HIV相关神经病理性疼痛常用止痛药在长期使用后反而加剧患者疼痛的机制。我们研究发现，Wnt5a/JNK及Wnt5a/Ca++信号通路是引发HIV-SN性疼痛的关键通路。以Wnt5a作为HIV-SN性疼痛治疗的靶点，可有效遏止gp120引发的HIV-SN性疼痛，有利于减少cART治疗过程中加重HIV引发HIV-SN的机会，还可有效避免HIV疼痛患者长期使用镇痛药所导致慢性疼痛状态加剧的现象。