Naltrexone and AIDS progression

纳曲酮与艾滋病进展

• 批准号: 8401395
• 负责人: GREGORY MICHAEL MILLER
• 金额: $ 21.88万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8401395
• 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

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. PUBLIC HEALTH RELEVANCE: Since the mid-1980's, the opioid antagonist naltrexone has been used at a low dose, off label, to attenuate AIDS progression by a relatively small group of HIV-infected individuals, and while there are strong anecdotal and testimonial reports of major beneficial effects in these patients, there has yet to be formal experimental investigation to validate its efficacy. This grant utilizes SIV-infected rhesus macaques as a translational research model to preclinically assess its efficacy, for the purpose of exploring whether this drug is beneficial in curtailing disease progression and AIDS.

描述（由申请人提供）：纳洛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的药物。自20世纪80年代中期以来，低剂量纳洛酮（LDN）已被用于标签外治疗HIV感染和预防AIDS。它有一群忠实的患者和医生，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的疗效。当给予未经治疗的HIV感染者时，LDN似乎可以稳定CD 4 + T细胞计数，保持淋巴细胞对有丝分裂原的反应性，并延缓进展为AIDS。可以想象，当在傍晚服用LDN时，可能会通过使HIV感染者的内源性昼夜阿片类药物激增正常化来发挥作用，这反过来又增强了他们免疫系统的功能。我们将利用SIV感染的猕猴的可用性，这些猕猴没有接受过任何SIV感染的治疗性混杂治疗，这些猕猴作为SIV疫苗开发研究的对照动物，这些研究由通过NEPRC管理其研究的各种研究者领导。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。将每天用0、0.05或0.3 mg/kg LDN处理24只SIV感染的恒河猴（n = 8/剂量）。将收集病毒RNA载量的纵向测量值，并使用重叠SIVmac 239肽通过Elispot和细胞内细胞因子染色测定来定量SIV特异性CD 4+和CD 8 + T细胞对整个SIV蛋白质组的应答。将通过多色流式细胞术组测定循环记忆CD 4+和CD 8 + T细胞表达的记忆、激活和耗竭标志物的特征，该多色流式细胞术组包括针对CD 3、CD 4、CD 28、CD 95、CCR 7、CCR 5、CD 69、HLA-DR和PD-1的抗体，并每2周监测一次。将进行全血细胞计数分析，以确定全血中的总淋巴细胞群。将使用总淋巴细胞群和每个亚群的频率计算每个时间点每？l血液中幼稚、中枢记忆和效应记忆CD 4 + T细胞群的细胞计数。还将测量α干扰素水平。μ-阿片受体是纳洛酮的主要靶点，并且人（N40 D）和恒河猴（P26 R）受体中的特定非同义多态性以惊人的平行方式改变配体结合并预测人和恒河猴中的纳洛酮敏感性（以减少酒精消耗）。因此，我们将检验恒河猴P26 R是LDN在SIV/猕猴模型中减少疾病进展的功效的决定因素的假设。我们将评估基因型/表型相关性，并在LDN治疗期间和治疗后测量内啡肽水平，揭示猕猴的昼夜节律模式以及LDN和SIV感染对这些模式的影响。如果LDN可以在高度翻译的SIV感染猕猴模型中减少艾滋病的进展，该研究可以验证一种低成本和安全的干预措施，以减少疾病进展，副作用很少或没有副作用。 公共卫生关系：自20世纪80年代中期以来，阿片样物质拮抗剂纳洛酮已经以低剂量、标签外使用，以减轻相对小的一组HIV感染个体的AIDS进展，并且尽管有关于这些患者中的主要有益效果的有力的轶事和证明报告，但还没有正式的实验研究来验证其功效。该基金利用SIV感染的恒河猴作为转化研究模型，以临床前评估其疗效，目的是探索这种药物是否 有益于抑制疾病进展和艾滋病。