Naltrexone and AIDS progression

描述（由申请人提供）：纳曲酮是一种阿片受体拮抗剂，是fda批准的药物，用于治疗海洛因过量和减少酗酒者的酒精摄入量。自20世纪80年代中期以来，低剂量纳曲酮（LDN）已被用于治疗HIV感染和预防艾滋病。它有一群忠实的患者和医生，他们声称从LDN中获得了显著的好处，但几乎没有科学数据可以证实或反驳LDN的功效。当给予未经治疗的hiv感染者时，LDN似乎稳定CD4+ T细胞计数，保持淋巴细胞对有丝分裂原的反应性，并延缓艾滋病的进展。可以想象，当在傍晚服用LDN时，可能会使hiv感染者体内钝化的内源性昼夜阿片激增正常化，从而增强其免疫系统的功能。我们将利用感染SIV的猕猴的可用性，这些猕猴没有接受任何针对SIV感染的治疗混淆治疗，它们是由通过NEPRC管理其研究的各种研究人员领导的SIV疫苗开发研究的对照动物。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。24只感染siv的恒河猴每天分别给予0、0.05或0.3 mg/kg LDN治疗（n = 8/剂量）。病毒RNA载量的纵向测量将被收集，SIV特异性CD4+和CD8+ T细胞对整个SIV蛋白质组的反应将通过Elispot和使用重叠SIVmac239肽的细胞内细胞因子染色测定进行定量。循环记忆CD4+和CD8+ T细胞表达的记忆、激活和耗竭标志物的特征将通过多色流式细胞仪检测，包括CD3、CD4、CD28、CD95、CCR7、CCR5、CD69、HLA-DR和PD-1抗体，并每2周监测一次。将进行全血细胞计数分析，以确定全血中总淋巴细胞群。总淋巴细胞群和每个亚群的频率将用于计算每个时间点每l血液中初始、中枢记忆和效应记忆CD4+ T细胞群的细胞计数。干扰素水平也将被测量。阿片受体是纳曲酮的主要靶点，人类（N40D）和恒河猴（P26R）受体的特异性非同义多态性以惊人的相似方式改变配体结合并预测人类和恒河猴对纳曲酮的敏感性（以减少酒精消耗）。因此，我们将在SIV/猕猴模型中验证恒河猴P26R是LDN抑制疾病进展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治疗期间和之后测量内啡肽水平，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可以在高度可翻译的siv感染的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，几乎没有副作用。

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.