FIV Testing of a CNS-Relevant Antiretroviral Compound

描述(由申请人提供)：特定目的HIV-1/AIDS的神经系统并发症尽管接受了HAART治疗，但仍然存在。目前的知识确定了神经元恶化的几个来源：(1)星形胶质细胞和小胶质细胞的直接病毒感染；(2)病毒感染的单核/巨噬细胞的渗透；(3)间接影响神经细胞的细胞因子失调；(4)血脑屏障的破坏；(5)抗原提呈异常导致自身免疫；(6)神经细胞的凋亡性自杀；(7)与HAART治疗相关的毒素。神经艾滋病患者迫切需要新的抗逆转录病毒治疗方法。这一目标是为了研究和开发一种治疗神经艾滋病的新疗法。根据初步研究，这种小分子表现出一种独特的分子作用，导致减少前病毒储存，并直接抑制病毒的产生。由于该化合物是血脑屏障可穿透的，它可能提供特别适合于中枢神经系统(CNS)慢病毒负荷的辅助治疗价值。工作假设是，FX101是一种新的抗逆转录病毒化合物，特别适用于神经艾滋病，独特地靶向慢病毒核衣壳蛋白。利用FIV模型，我们试图研究抗病毒的效果，重点是中枢神经系统的隔室，并将这些发现与所提出的作用机制联系起来。拟议的研究旨在实现四个目标：1)建立FX101在猫体内的安全性和药代动力学，包括对中枢神经系统的渗透。2)测定FX101对血浆、脑脊液、T细胞亚群和脑组织FIV负荷的影响。3)评价FX101在巨噬细胞中的摄取和分布及其抑制病毒产生的能力。4)检查和比较接触FX101期间产生的病毒粒子后代和核衣壳蛋白。我们建议检查这种新化合物的药代动力学、安全性和抗逆转录病毒疗效，以应用于与中枢神经系统相关的HIV抗逆转录病毒化合物。

DESCRIPTION (provided by applicant): Specific Aims Neurological complications of HIV-1/AIDS persist despite HAART therapies. Current knowledge identifies several sources of neuronal aggravation: (1) direct virus infection of astrocytes and microglial cells; (2) infiltratin of virus-infected monocyte/macrophages; (3) cytokine dysregulation indirectly affecting nerve cells; (4) breakdown of the blood-brain-barrier; (5) abnormal antigen-presentation leading to autoimmunity; (6) apoptotic suicide of neuronal cells and (7) toxins associated with HAART therapies. Novel antiretroviral therapeutic approaches are urgently needed for individuals suffering from NeuroAIDS. This goal is to investigate and develop a novel therapeutic for the treatment of NeuroAIDS. Based upon preliminary studies, this small molecule exhibits a unique molecular action resulting in reductions to the proviral reservoir together with direct inhibition f virus productions. Since the compound is blood-brain barrier penetrable, it potentially affords adjunctive therapeutic value specifically appropriate for central nervous system (CNS) lentivirus burdens. The working hypothesis is that FX101 is a novel antiretroviral compound especially suited for NeuroAIDS, uniquely targeting lentiviral nucleocapsid proteins. Using the FIV model, we seek to investigate antiviral efficacies with emphasis to the CNS compartment and to relate these findings to the proposed mechanism of action. The proposed studies are designed to accomplish four goals: 1) Establish safety and pharmacokinetics of FX101 in cats, including penetration into the CNS. 2) Measure effects of FX101 on FIV burden in plasma, CSF, T-cell subsets and brain tissue. 3) Evaluate the uptake and distribution of FX101 in macrophages and its ability to suppress virus production. 4) Examine and compare virion progeny and nucleocapsid proteins produced during exposure to FX101. We propose to examine pharmacokinetic, safety and antiretroviral efficacy of this novel compound towards application of a CNS-relevant antiretroviral compound for HIV.