FIV Testing of a CNS-Relevant Antiretroviral Compound

描述（由申请人提供）：特定目的尽管HAART治疗，HIV-1/AIDS的神经系统并发症仍然存在。目前的知识确定了神经元恶化的几种来源：(1)星形胶质细胞和小胶质细胞的直接病毒感染；(2)病毒感染单核细胞/巨噬细胞的浸润；(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)抗原呈递异常导致自身免疫；(6)神经元细胞凋亡自杀和(7)与HAART疗法相关的毒素。神经艾滋病患者迫切需要新的抗逆转录病毒治疗方法。我们的目标是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，导致原病毒库的减少，并直接抑制病毒的产生。由于该化合物可穿透血脑屏障，因此它具有潜在的辅助治疗价值，特别适用于中枢神经系统（CNS）慢病毒负荷。工作假设是FX101是一种特别适合于神经艾滋病的新型抗逆转录病毒化合物，独特地靶向慢病毒核衣壳蛋白。使用FIV模型，我们试图研究抗病毒效果，重点是中枢神经系统室，并将这些发现与提出的作用机制联系起来。拟建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)评价巨噬细胞中FX101的摄取和分布及其抑制病毒产生的能力。4)检测并比较暴露于FX101时产生的病毒粒子子代和核衣壳蛋白。我们建议研究这种新化合物的药代动力学、安全性和抗逆转录病毒疗效，以期应用于与中枢神经系统相关的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. PUBLIC HEALTH RELEVANCE: This research proposal examines both efficacy and a novel mechanism of action of a blood-brain- barrier penetrable therapeutic useful in the treatment of HIV/AIDS, reducing proviral reservoirs in peripheral blood mononuclear cells and cerebrospinal measures of viremia. It is expected that this work will reduce the burden of neurological diseases impacting the central nervous system as a consequence of lentiviral infections and associated pathologies, leading to better treatments for HIV/AIDS-Associated Neuropsychological Disorders.