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

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

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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（请参阅说明）：尽管在艾滋病患者中广泛使用抗逆转录病毒疗法，但与HIV相关的神经认知障碍（手）的患病率（包括无症状的神经认知障碍（ANI），轻度神经认知障碍（MND）和HER相关性痴呆症（有），仍然很高。即使是轻度的神经认知障碍形式也可能影响H1V+个体中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可能在治疗个体中发展或持续存在的原因尚不清楚，但是未能消除病毒储存术和不足的药物渗透CNS可能在允许低水平的病毒复制持续存在方面发挥作用。由于这些原因，治疗HIV脑炎（HIVE）的新型化合物的发展是重要生物医学重要性的目标。在这个项目中，我们开始对非人类灵长类动物进行概念验证研究，以测试新型的抗VIF候选药物，以支持加速基本和转化的发现，以促进新药治疗药物的发展。 HIV-1 VIF是HLV-1复制干预的高度吸引力但未实现的治疗靶标。 HIV-1 VIF对于体外的灵长类动病毒复制至关重要。我们已经确定了铅VIF拮抗剂（RN18），该拮抗剂表现出针对VIF依赖性病毒复制的精致抗病毒特异性。我们计划评估在神经辅助剂模型中，在主要研究中最有前途的RN18类似物的体内功效。 VIF拮抗剂将在SIV诱导的脑炎（SIVE）的猴子模型中检查具有啮齿动物中最理想的抗病毒活性，经过验证的作用机理（项目1和2）以及可接受的毒性和药代动力学特征。我们预计每组6只动物对2-3个VIF拮抗剂/年进行体内分析。