Preclinical Development of HIV-1 Vif Antagonists - Project 3

HIV-1 Vif 拮抗剂的临床前开发 - 项目 3

基本信息

批准号：
8723305
负责人：
NANCY J SCHULTZ-DARKEN
金额：
$ 37.92万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8723305
关键词：
AIDS Dementia Complex AIDS neuropathy Acquired Immunodeficiency Syndrome Adherence Animals Anti-Retroviral Agents Antiviral Agents Biological Markers CD4 Lymphocyte Count Cells Central Nervous System Diseases Consequences of HIV DNA Markers Deamination Development Disease Disease Progression Drug Kinetics Drug Targeting Encephalitis Exhibits Failure Goals HIV HIV Infections HIV encephalitis HIV-1 Highly Active Antiretroviral Therapy Immunohistochemistry Immunologic Deficiency Syndromes Impairment In Situ Hybridization In Vitro Individual Infection Inflammation Instruction Intervention Lead Macaca Macaca mulatta Massachusetts Modeling Monkeys Neurocognitive Neuropathogenesis Pathology Patients Penetration Pharmaceutical Preparations Plasma Play Preclinical Drug Evaluation Preclinical Testing Prevalence Primate Lentiviruses Proteins Quality of life Rodent Role SIV SIV encephalitis Severity of illness Specificity Testing Therapeutic Therapeutic Agents Toxic effect Universities Viral Viral Genes Viral Load result Virus Work analog cytokine drug candidate in vivo inhibitor/antagonist medical schools mild neurocognitive impairment nervous system disorder nonhuman primate novel novel therapeutics pre-clinical prevent small molecule therapeutic target vaccine development vif Gene Products viral DNA viral RNA

项目摘要

PROJECT SUMMARY (See instructions): Despite the widespread use of anti-retroviral therapy in AIDS patients, the prevalence of HIV-Associated Neurocognitive Disorders (HAND), including Asymptomatic Neurocognitive Impairment (ANI), Mild Neurocognitive Disorder (MND), and HIV-Associated Dementia (HAD), remains significantly high. Even mild forms of neurocognitive impairment may impact quality of life and antiretroviral drug adherence in H1V+ individuals (McArthur, 2004). The reason CNS complications may develop or persist in treated individuals is not known, but failure to eliminate viral reservoirs and inadequate drug penetration to the CNS could play a role in allowing low level viral replication to persist. For these reasons the development of novel compounds to treat HIV encephalitis (HIVE) is an objective of significant biomedical importance. In this project, we embark on proof-of-concept studies in nonhuman primates to test novel anti-Vif candidate drugs in support of efforts to accelerate basic and translational discoveries toward the advancement of new drug therapeutics for HAND. HIV-1 Vif is a highly attractive yet unrealized therapeutic target for the intervention of HlV-1 replication. HIV-1 Vif is essential for primate lentivirus replication in vitro. We have identified a lead Vif antagonist (RN18) that exhibits exquisite antiviral specificity against Vif-dependent viral replication. We plan to evaluate the in vivo efficacy ofthe most promising RN18 analogs in proof-of principal studies in a simian model of neuroAIDS. Vif antagonists with the most desirable antiviral activities, validated mechanism of action (Projects 1 and 2), and acceptable toxicity and pharmacokinetic profiles in rodents will be examined for in vivo antiviral activity in a monkey model of SIV-induced encephalitis (SIVE). We anticipate in vivo analysis of 2-3 Vif antagonists/year in groups of 6 animals each.

项目摘要（参见说明）：尽管抗逆转录病毒治疗在艾滋病患者中广泛使用，但艾滋病毒相关神经认知障碍（HAND）的患病率仍然很高，包括无症状神经认知障碍（ANI）、轻度神经认知障碍（MND）和艾滋病毒相关痴呆（HAD）显着高。即使是轻微的神经认知障碍也可能影响 H1V+ 个体的生活质量和抗逆转录病毒药物的依从性（McArthur，2004）。中枢神经系统并发症在治疗个体中可能出现或持续存在的原因尚不清楚，但未能消除病毒库和药物对中枢神经系统的渗透不足可能会导致低水平病毒复制持续存在。由于这些原因，开发治疗艾滋病毒脑炎（HIVE）的新型化合物是具有重要生物医学意义的目标。在这个项目中，我们开始在非人类灵长类动物中进行概念验证研究，以测试新型抗 Vif 候选药物，以支持加速基础和转化发现的努力，以推动 HAND 新药物疗法的发展。 HIV-1 Vif 是干预 HIV-1 复制的一个极具吸引力但尚未实现的治疗靶点。 HIV-1 Vif 对于灵长类慢病毒体外复制至关重要。我们已经鉴定出一种主要的 Vif 拮抗剂 (RN18)，它对 Vif 依赖性病毒复制表现出精致的抗病毒特异性。我们计划在神经艾滋病猿模型的原理验证研究中评估最有前途的 RN18 类似物的体内功效。 Vif 拮抗剂具有最理想的抗病毒活性、经过验证的作用机制（项目 1 和 2）以及在啮齿类动物中可接受的毒性和药代动力学特征，将在 SIV 诱发的脑炎 (SIVE) 猴模型中检查其体内抗病毒活性。我们预计每年对 2-3 个 Vif 拮抗剂进行体内分析，每组 6 只动物。