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）导致自身免疫的异常抗原呈递;（6）神经元细胞的凋亡性自杀和（7）与HAART疗法相关的毒素。新的抗逆转录病毒治疗方法是迫切需要的个人患有神经艾滋病。本研究的目的是研究和开发一种新的治疗NeuroAIDS的药物。基于初步研究，这种小分子表现出独特的分子作用，导致减少前病毒库以及直接抑制病毒产生。由于该化合物是血脑屏障可穿透的，因此它可能提供特别适用于中枢神经系统（CNS）慢病毒负荷的连续治疗价值。工作假设是，FX 101是一种新的抗逆转录病毒化合物，特别适用于神经艾滋病，独特的靶向慢病毒核衣壳蛋白。使用FIV模型，我们试图研究抗病毒疗效，重点是中枢神经系统的隔室，并将这些发现与拟议的作用机制。拟定研究旨在实现四个目标：1）确定FX 101在猫中的安全性和药代动力学，包括渗透到CNS中。2)测量FX 101对血浆、CSF、T细胞亚群和脑组织中FIV负荷的影响。3)评价FX 101在巨噬细胞中的摄取和分布及其抑制病毒产生的能力。4)检查并比较暴露于FX 101期间产生的病毒体子代和核衣壳蛋白。我们建议研究这种新型化合物的药代动力学，安全性和抗逆转录病毒疗效，以应用CNS相关的抗逆转录病毒化合物治疗HIV。 公共卫生相关性：这项研究计划检查了一种可穿透血脑屏障的治疗药物的疗效和一种新的作用机制，该药物可用于治疗HIV/AIDS，减少外周血单核细胞中的前病毒库和病毒血症的脑脊液措施。预计这项工作将减少因慢病毒感染和相关病理而影响中枢神经系统的神经系统疾病的负担，从而更好地治疗艾滋病毒/艾滋病相关的神经心理障碍。

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.