Naltrexone and AIDS progression

描述(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酒精摄入量。自20世纪80年代中期S以来，小剂量纳曲酮被用于标签外治疗艾滋病毒感染和预防艾滋病。它有一批患者和医生的忠实追随者，他们声称LDN具有显著的好处，但几乎没有可用的科学数据来验证或驳斥LDN的有效性。当给予未经治疗的艾滋病毒感染者时，LDN似乎可以稳定CD4T细胞计数，保持淋巴细胞对有丝分裂原的反应性，并延缓向艾滋病的进展。可以想象，如果在傍晚早些时候服用LDN，可能会导致艾滋病毒感染者体内迟钝的内源性阿片类药物激增正常化，进而增强他们的免疫系统功能。我们将利用感染SIV的猕猴的可用性，这些猕猴没有接受过任何治疗SIV感染的混合治疗，它们作为SIV疫苗开发研究的对照动物，由不同的研究人员领导，他们通过NEPRC管理他们的研究。我们不会对这些动物实施安乐死，而是严格确定LDN在延缓艾滋病进展和增强免疫功能方面的作用。24只感染SIV的恒河猴每天将接受0、0.05或0.3 mg/kg的LDN治疗(n=8/剂)。将收集病毒RNA载量的纵向测量，并将通过ELISPOT和使用重叠的SIVmac239肽的细胞内细胞因子染色分析来定量SIV特异性的CD4和CD8 T细胞对整个SIV蛋白质组的反应。循环记忆CD4和CD8 T细胞表达的记忆、激活和衰竭标志物的特征将由一个多色流式细胞仪小组确定，该小组包括CD3、CD4、CD28、CD95、CCR7、CCR5、CD69、HLA-DR和PD-1抗体，并每两周监测一次。将进行完整的血细胞计数分析，以确定全血中的淋巴细胞总数。淋巴细胞总数和每个亚群的频率将被用来计算每个时间点每个L血液中幼稚、中央记忆和效应记忆的CD4T细胞数量。还将测量α干扰素水平。Mu-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以惊人的平行方式改变配基结合并预测纳曲酮的敏感性(减少酒精消耗)。因此，我们将在SIV/猕猴模型中检验这一假设，即恒河猴P26R是LDN在抑制疾病进展方面的有效性的决定因素。我们将评估在LDN治疗期间和之后的基因型/表型相关性和内啡肽水平，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感染的猕猴模型中减少艾滋病的进展，这项研究可以验证一种低成本和安全的干预措施，以遏制疾病的进展，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.