Naltrexone and AIDS progression

纳曲酮与艾滋病进展

基本信息

批准号：
8466305
负责人：
GREGORY MICHAEL MILLER
金额：
$ 21万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8466305
关键词：
Acquired Immunodeficiency Syndrome Adverse effects Alcohol consumption Animals Antibodies Attenuated Biological Assay Blood Brain CCR5 gene CD28 gene CD3 Antigens CD4 Positive T Lymphocytes CD8B1 gene Cell Count Cells Chronic Phase Circadian Rhythms Color Complete Blood Count Control Animal Data Dimerization Disease Progression Dose Drug usage Employee Strikes Endorphins FDA approved Failure Flow Cytometry Frequencies Genetic Polymorphism Genotype Grant HIV HIV Infections HIV-1 HLA-DR Antigens Health Human Immune Immune system Immunity Individual Infection Interferon-alpha Intervention Investigation Label Lead Ligand Binding Lymphocyte Macaca Macaca mulatta Measures Mediating Memory Mitogens Modeling Monitor Monkeys Naltrexone Narcotic Antagonists New England Opioid Opioid Peptide Opioid Receptor Patient Self-Report Patients Pattern Peptides Pharmaceutical Preparations Pharmacogenomics Phenotype Phosphorylation Plasma Population Postdoctoral Fellow Primates Proteome Protocols documentation Reporting Research Research Personnel Route SIV SIV Vaccines Simian Acquired Immunodeficiency Syndrome Staining method Stains T cell response T-Cell Activation T-Lymphocyte TNFRSF6 gene Testing Therapeutic Time Translational Research Vaccines Variant Viral Load result Virus Whole Blood Work cost cytokine desensitization endogenous opioids exhaustion heroin overdose immune function memory CD4 T lymphocyte mu opioid receptors prevent problem drinker receptor receptor sensitivity research and development vaccine development viral RNA

项目摘要

DESCRIPTION (provided by applicant): Naltrexone, an opioid receptor antagonist, is an FDA-approved drug used for treating heroin overdose and decreasing alcohol intake in alcoholics. Since the mid-1980's, low dose naltrexone (LDN) has been used off- label for treating HIV infection and preventing AIDS. It has a loyal following of patients and doctors who claim remarkable benefits from LDN, yet there has been little scientific data available to validate or refute LDN efficacy. When administered to untreated HIV-infected individuals, LDN appears to stabilize CD4+ T cell counts, preserve lymphocyte responsiveness to mitogens and delay progression to AIDS. Conceivably, when taken in the early evening LDN may work by causing a normalization of a blunted endogenous circadian opioid surge in HIV-infected individuals, which in turn enhances the function of their immune system. We will take advantage of an availability of SIV-infected macaques that have not received any therapeutic confounding treatments for their SIV infection, having served as control animals for SIV vaccine development research led by various investigators who manage their research through the NEPRC. Rather than euthanize these animals, we will rigorously determine the effect of LDN in attenuating AIDS progression and enhancing immune function. Twenty-four SIV-infected rhesus macaques will be treated with 0, 0.05 or 0.3 mg/kg LDN daily (n = 8/dose). Longitudinal measures of viral RNA loads will be collected, and SIV-specific CD4+ and CD8+ T cell responses to the entire SIV proteome will be quantitated by Elispot and intracellular cytokine staining assays using overlapping SIVmac239 peptides. The profile of memory, activation, and exhaustion markers expressed by circulating memory CD4+ and CD8+ T cells will be determined by a polychromatic flow cytometry panel that includes antibodies to CD3, CD4, CD28, CD95, CCR7, CCR5, CD69, HLA-DR and PD-1, and monitored every 2 weeks. A complete blood count analysis will be performed to determine the total lymphocyte population in whole blood. The total lymphocyte population and the frequency of each subset will be used to calculate cell counts for naive, central memory and effector memory CD4+ T cell populations per ¿l of blood at each time point. Alpha interferon levels will also be measured. The mu-opioid receptor is a major target of naltrexone, and specific nonsynonymous polymorphisms in both the human (N40D) and rhesus monkey (P26R) receptor alter ligand binding and predict naltrexone sensitivity (to curtail alcohol consumption) i both humans and rhesus monkeys in a strikingly parallel manner. Accordingly, we will test the hypothesis that rhesus monkey P26R is a determinant of LDN efficacy in curtailing disease progression in the SIV/macaque model. We will assess genotype/phenotype associations and measure endorphin levels during and following treatment with LDN, revealing circadian patterns in the macaque and effects of LDN and SIV infection on these patterns. If LDN can reduce the progression of AIDS in the highly translational SIV-infected macaque model, the research could validate a low cost and safe intervention to curtail disease progression with little or no side effects.

描述（由申请人提供）：纳曲酮是一种阿片受体拮抗剂，是 FDA 批准的用于治疗海洛因过量和减少酗酒者酒精摄入量的药物。自 20 世纪 80 年代中期以来，低剂量纳曲酮 (LDN) 已在标签外使用。用于治疗艾滋病毒感染和预防艾滋病，它拥有一批忠实的患者和医生，他们声称 LDN 具有显着的益处，但几乎没有科学数据可以验证或反驳 LDN 的功效。对于未经治疗的 HIV 感染者，LDN 似乎可以稳定 CD4+ T 细胞计数，保持淋巴细胞对有丝分裂原的反应性，并延缓艾滋病进展。可以想象，在傍晚服用 LDN 可能会通过使 HIV 内源性阿片类药物的昼夜节律激增正常化而发挥作用。 - 感染个体，这反过来又增强了其免疫系统的功能。我们将利用尚未接受任何治疗性混杂治疗的感染 SIV 的猕猴。我们将严格确定 LDN 在减缓艾滋病进展和增强免疫功能方面的作用，而不是对这些动物实施安乐死。每天使用 0、0.05 或 0.3 mg/kg LDN 治疗 24 只感染 SIV 的恒河猴（n = 8/剂量）。将收集病毒 RNA 负载，并使用重叠的 SIVmac239 肽通过 Elispot 和细胞内细胞因子染色测定来定量 SIV 特异性 CD4+ 和 CD8+ T 细胞对整个 SIV 蛋白质组的反应。循环表达的记忆、激活和耗竭标记物的概况。记忆 CD4+ 和 CD8+ T 细胞将通过多色流式细胞仪检测，其中包括 CD3、CD4、CD28、CD95、 CCR7、CCR5、CD69、HLA-DR 和 PD-1，每 2 周进行一次全血细胞计数分析，以确定全血中的淋巴细胞总数和每个亚群的频率。用于计算每个 ¿ 的幼稚、中央记忆和效应记忆 CD4+ T 细胞群的细胞计数还将测量每个时间点的 l 血液中的α干扰素水平。mu-阿片受体是纳曲酮的主要靶标，人类 (N40D) 和恒河猴 (P26R) 受体中的特定非同义多态性会改变配体结合和。以惊人的平行方式预测人类和恒河猴的纳曲酮敏感性（以减少饮酒）。因此，我们将检验恒河猴的假设。 P26R 是 LDN 在 SIV/猕猴模型中抑制疾病进展的功效的决定因素。我们将评估基因型/表型关联并测量 LDN 治疗期间和治疗后的内啡肽水平，揭示猕猴的昼夜节律模式以及 LDN 和 SIV 感染对疾病进展的影响。如果 LDN 可以在高度转化的 SIV 感染的猕猴模型中减少艾滋病的进展，那么该研究可以验证一种低成本且安全的干预措施来遏制疾病进展。副作用很小或没有。