Modulation of Cell-Mediated Immune Function by Opiates

描述(由申请人提供)：在认识到静脉注射吸毒者是发展为艾滋病的高危群体后，推测海洛因可能通过阿片介导的免疫抑制和病毒表达的增强，在艾滋病毒-1的发病机制中起辅助因素的作用，包括发展神经艾滋病。尽管有大量支持证据，但阿片类药物滥用对HIV-1发病机制的影响仍存在争议。药理学方面的考虑被认为是流行病学和实验数据相互矛盾的一种解释。这项研究建议检验的主要假设是，药物因素，如浓度和时间依赖的反应以及与其他药物(即大麻和抗逆转录病毒药物)的相互作用，将显著影响海洛因的主要代谢物吗啡和其他u阿片受体(MOR)配体如何影响HIV-1致病的两个关键方面：1)CD4和小胶质细胞中的病毒表达；2)gp120蛋白诱导CD4和神经细胞凋亡。为了验证这一假设，我们设计了三个具体的实验目标：1)研究MOR配体和大麻素对CD4和小胶质细胞培养中HIV-1表达的影响；2)在相同的细胞培养模型中，研究吗啡是否改变了抗逆转录病毒药物的活性；以及3)研究MOR配体和大麻素对gp120(IIIB)诱导的CD4和神经元凋亡的影响。之所以选择大麻素进行这些研究，是因为大麻素类大麻被广泛滥用，而且有文献表明，大麻素也会改变免疫系统，并与阿片类药物产生相互作用。我们在研究中选择的抗逆转录病毒药物齐多夫定(AZT)和依地那韦通常用于治疗HIV-1感染的阿片依赖患者。为这一研究项目设计的研究有望为阿片剂和大麻类药物影响艾滋病毒-1免疫病理和神经发病机制提供新的见解，长期目标是开发治疗这种病毒造成的毁灭性感染的新方法。

DESCRIPTION (provided by applicant): Following recognition that intravenous drug users are a high risk group for development of AIDS, it was postulated that heroin could act as a cofactor in the pathogenesis of HIV-1, including development of neuroAIDS, via opiate-mediated immunosuppression and potentiation of viral expression. Despite a large body of supportive evidence, the impact of opiate abuse on HIV-1 pathogenesis remains controversial. Pharmacological considerations have been proposed as one explanation for the conflicting epidemiological and experimental data. The principal hypothesis to be tested in this research proposal is that pharmacologic factors, such as, concentration- and time-dependent responses and interactions with other drugs (i.e., cannabinoids and antiretroviral agents), will markedly influence how morphine, a major metabolite of heroin, and other mu-opioid receptor (MOR) ligands affect two critically important aspects of HIV-1 pathogenesis: 1) viral expression in CD4 and microglial cells, and 2) gp120 protein-induced apoptosis of CD4 and neuronal cells. To test this hypothesis, experiments have been designed that address three specific aims: 1) to investigate the effects of MOR ligands and cannabinoids on HIV-1 expression in CD4 and microglial cell cultures, 2) to investigate whether morphine alters the activity of antiretroviral drugs in these same cell culture models, and 3) to investigate the effects of MOR ligands and cannabinoids on gp120(IIIB)-induced apoptosis of CD4 and neurons. Cannabinoids have been chosen for these studies because of the widespread abuse of the cannabinoid marijuana and a literature demonstrating that cannabinoids also alter the immune system and have interactive effects with opioids. The antiretroviral agents we have chosen for our studies, zidovudine (AZT) and indinavir, are commonly used to treat HIV-1-infected, opiate-dependent patients. The studies designed for this research project promise to provide new insights into the mechanisms whereby opiates and cannabinoids affect the immunopathogenesis and neuropathogenesis of HIV-1 with the long-term goal of developing new approaches to the treatment of the devastating infection caused by this virus.