HIV and antiretroviral toxic neuropathy

描述（由申请人提供）：人类免疫缺陷病毒（HIV）相关感觉神经病变（H1V-SN）是HIV感染的主要神经系统并发症，尽管使用了高效抗逆转录病毒治疗（HAART），但这种HIV感染并发症的发生率和流行率仍然很高。HIV相关的感觉神经病变通常分为由于HIV感染本身引起的远端对称多神经病变（DSP）和由于使用双脱氧核苷（DDX）药物引起的抗逆转录病毒毒性神经病变（ATM）。在临床上，这两种情况是相似的，并且可能在HIV-SN的发病机制中起协同作用。目前，还没有针对逆转或减缓这些影响艾滋病毒/艾滋病患者生活质量的痛苦神经病变进展的治疗方法。在此资助的前一个周期中，我们开发了ATN和DSP的体外模型，并确定了存在于外周神经系统（PNS）中的一种新的内源性神经保护途径。这一进展与HIV-SN转基因小鼠模型的开发相结合，该模型将有助于研究HIV-SN的潜在机制。此外，我们发现促红细胞生成素是HIV-SN的潜在治疗靶点。在当前的应用中，我们建议继续研究DDX药物治疗转基因小鼠远端轴突变性的细胞机制，以及HIV蛋白和DDX药物引起神经元功能障碍和轴突变性的分子机制。我们将研究参与神经元功能障碍和死亡的各种线粒体途径在介导HIV包膜蛋白gp120和DDX神经毒性中的作用。我们将使用HIV-SN动物模型来开发HIV-SN治疗效果的生物标志物。最后，我们将探索由缺氧诱导因子（HIF）、hsp70通路激活因子和亲环蛋白配体调控的神经营养基因的治疗潜力，以开发针对hiv相关感觉神经病变的新疗法。这些目标与我们在诊所服务的患者群体高度相关，因为对于与HIV感染和DDX药物使用相关的疼痛性感觉神经病变没有有效的治疗方法。

DESCRIPTION (provided by applicant): Human immunodeficiency virus (HIV) associated sensory neuropathies (H1V-SN) are major neurological complications of the HIV infection and despite the use of highly active antiretroviral therapy (HAART), the incidence and prevalence of this often painful complication of HIV infections remains high. HIV associated sensory neuropathies are often divided into distal symmetric polyneuropathy (DSP) due to the HIV infection per se and antiretroviral toxic neuropathy (ATM) due to the use of dideoxynucleoside (DDX) drugs. Clinically both conditions are similar and likely to have a synergistic role in the pathogenesis of HIV-SN. Currently, there are no therapies aimed at reversing or slowing the progression of these painful neuropathies that affect the quality of life of HIV/AIDS patients. In the previous cycle of this grant, we have developed in vitro models of ATN and DSP and identified a novel endogenous neuroprotective pathway that exist in the peripheral nervous system (PNS). This progress is coupled to the development of a transgenic mouse model of HIV-SN that will be useful in examining the underlying mechanisms of HIV-SN. Furthermore, we identified, erythropoietin as a potential therapeutic target for HIV-SN. In the current application we propose to continue our investigations into the cellular mechanisms of distal axonal degeneration in transgenic mice treated with DDX drugs as well as molecular mechanisms by which HIV proteins and DDX drugs cause neuronal dysfunction and axonal degeneration. We will examine the role of various mitochondrial pathways involved in neuronal dysfunction and death in mediating HIV envelope protein gp120 and DDX neurotoxicity. We will use the animal model of HIV-SN to develop biomarkers of treatment effects in HIV-SN. Finally, we will explore the therapeutic potential of neurotrophic genes regulated by hypoxia inducible factor (HIF), activators of the hsp70 pathway, and cyclophilin ligands to develop novel therapies for HIV-associated sensory neuropathies. These goals are highly relevant to the patient population we serve in the clinic as there are no effective therapies for the painful sensory neuropathy associated with HIV infection and use of DDX drugs.