NEURO-AIDS IN OPIATE DEPENDENT RHESUS MACAQUES

阿片依赖恒河猴的神经艾滋病

• 批准号: 6523075
• 负责人: PAUL DAVID CHENEY
• 金额: $ 51.51万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6523075
• 关键词: AIDS dementia complex; Macaca mulatta; behavior test; disease /disorder model; drug abuse; drug withdrawal; evoked potentials; lymphocyte; macrophage; male; microglia; morphine; pathologic process; receptor expression; simian AIDSs; simian immunodeficiency virus; virus receptors; virus replication

HIV-1 not only attacks the immune system leading to systemic AIDS but also enters the brain where it indirectly injures neurons and produces a constellation of symptoms known collectively as neuro- AIDS. Substantial evidence suggests that opiates may exacerbate the severity of HIV-1 disease and accelerate its progression to AIDS. In contrast, other studies have suggested that opiate exposure may have a protective effect and actually reduce the severity of disease and slow its progression to AIDS. Despite the importance of better understanding the linkages between drug abuse and the development of AIDS as well as AIDS-related neurological disease, there have been few studies of these relationships in animal models. To date, only two published studies have taken advantage of the simian immunodeficiency virus (SIV) infected macaque model, even though this model best reproduces the immunological, virological and neurological features of human HIV-disease. Over the past several years, we have focused our efforts on developing macaque models of neuro- AIDS. We recently completed studies on a cohort of nine rhesus macaques infected with neurovirulent strains of SIVmac. All monkeys in this cohort showed behavioral and neurophysiological impairments when tested on a battery that included reaction time, working memory and motor skill tasks as well as sensory and motor evoked potentials. Neuropathological and stereological studies in the same monkeys demonstrated microglial nodules and multinucleate giant cells, the hallmarks of HIV brain infection, as well as significant neuronal cell loss. Recently, several pathogenic strains of chimeric simian-human immunodeficiency virus have been developed that contain the tat, rev, vpu, and env of HIV-1 in a genetic background of SIVmac239. One of these viruses, SHIVKU-2MC4, causes rapid CD4+ T cell depletion and neuro-AIDS following inoculation into rhesus macaques. This virus represents a significant advance as an animal model because the Env of HIV-1 has been implicated in HIV-1-induced neuropathogenesis and because the Env proteins of SIV and HIV-1 are only distantly related. In this application, we propose four specific aims that focus on the behavioral, neurological, immunological and virological consequences of opiate-dependence in SHIV-infected rhesus macaques. A fifth specific aim will investigate the cellular and molecular mechanisms by which morphine influences viral replication and co-receptor expression in lymphocyte and macrophage populations.

HIV-1不仅攻击免疫系统导致系统性艾滋病，而且还进入大脑，在那里它间接损伤神经元并产生一系列统称为神经艾滋病的症状。 大量证据表明，阿片类药物可能加剧HIV-1疾病的严重程度，并加速其发展为艾滋病。 相反，其他研究表明，阿片类药物暴露可能具有保护作用，实际上可以减轻疾病的严重程度，减缓其向艾滋病的进展。 尽管必须更好地了解药物滥用与艾滋病的发展以及与艾滋病有关的神经系统疾病之间的联系，但在动物模型中对这些关系的研究很少。 迄今为止，只有两个已发表的研究利用了猴免疫缺陷病毒（SIV）感染的猕猴模型，即使这个模型最好地再现了人类艾滋病的免疫学，病毒学和神经学特征。 在过去的几年里，我们一直致力于开发神经艾滋病的猕猴模型。 我们最近完成了对9只感染SIVmac神经毒力株的恒河猴的研究。 当对包括反应时间、工作记忆和运动技能任务以及感觉和运动诱发电位的电池进行测试时，该队列中的所有猴子都显示出行为和神经生理学障碍。 对同一只猴子进行的神经病理学和体视学研究显示，小胶质细胞结节和多核巨细胞是艾滋病毒脑感染的标志，以及显著的神经元细胞损失。 最近，已经开发了几种嵌合猴-人免疫缺陷病毒的致病株，其在SIVmac 239的遗传背景中含有HIV-1的达特、rev、vpu和env。 这些病毒之一SHIVKU-2 MC 4在接种到恒河猴中后引起快速的CD 4 + T细胞耗竭和神经艾滋病。 这种病毒作为动物模型代表了一个重大进展，因为HIV-1的Env与HIV-1诱导的神经发病机制有关，而且SIV和HIV-1的Env蛋白只有远亲关系。 在这个应用程序中，我们提出了四个具体的目标，专注于行为，神经，免疫和病毒学的后果，阿片类药物依赖性的SHIV感染的恒河猴。 第五个具体目标将研究吗啡影响淋巴细胞和巨噬细胞群体中病毒复制和共受体表达的细胞和分子机制。