NEURO-AIDS IN OPIATE DEPENDENT RHESUS MACAQUES

HIV-1不仅攻击导致全身性艾滋病的免疫系统，而且还会进入大脑，在那里间接损伤神经元，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艾滋病毒-1疾病的严重程度并加速其向艾滋病的进展。与此相反，其他研究表明，接触阿片类药物可能具有保护作用，实际上可以降低疾病的严重程度，减缓其向艾滋病发展的速度。尽管更好地了解药物滥用与艾滋病以及与艾滋病有关的神经系统疾病的发展之间的联系很重要，但在动物模型中对这些关系的研究很少。迄今为止，只有两项已发表的研究利用了猴免疫缺陷病毒（SIV）感染的猕猴模型，尽管这种模型最好地再现了人类hiv疾病的免疫学、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。我们最近完成了一组9只恒河猴感染SIVmac神经毒性毒株的研究。在包括反应时间、工作记忆、运动技能任务以及感觉和运动诱发电位在内的电池测试中，这一队列中的所有猴子都表现出行为和神经生理障碍。在这些猴子身上进行的神经病理学和体视学研究表明，小胶质结节和多核巨细胞是HIV脑感染的标志，同时也出现了显著的神经元细胞损失。最近，一些嵌合猿人免疫缺陷病毒的致病毒株被开发出来，这些毒株含有HIV-1的tat、rev、vpu和env，其遗传背景为SIVmac239。其中一种病毒SHIVKU-2MC4在恒河猴体内接种后可引起CD4+ T细胞快速耗竭和神经艾滋病。该病毒作为动物模型是一项重大进展，因为HIV-1的Env与HIV-1诱导的神经发病机制有关，而且SIV的Env蛋白与HIV-1只有远亲关系。在这个应用中，我们提出了四个具体的目标，集中在行为，神经学，免疫学和病毒学的后果阿片类药物依赖在shiv感染恒河猴。第五个特定目的是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。

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.