NEUROIMMUNOLOGY AND NEUROPATHOGENESIS OF HIV INFECTION

HIV 感染的神经免疫学和神经发病机制

• 批准号: 3803246
• 负责人: L VITKOVIC
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3803246
• 关键词: HIV infections; astrocytes; colony stimulating factor; gene expression; human immunodeficiency virus 1; interleukin 1; interleukin 6; laboratory mouse; microglia; murine leukemia virus; nervous system disorder; oligodendroglia; psychoneuroimmunology; tissue /cell culture; transforming growth factors; virus infection mechanism

We have demonstrated that human astrocytes and two cell lines derived therefrom are capable of secreting cytokines known to be able to regulate human immunodeficiency virus (HIV) expression:interleukin-6 (IL-6), transforming growth factor-beta (TGF-Beta) and granulocyte macrophage-colony stimulating factor. The secretion of all three cytokines is stimulated in time- and dose-dependant manner by IL-1. IL-1 was found to stimulate TGF-Beta secretion by oligodendrocytes and microglia. These results suggest that the secretion of cytokines by glial cells may stimulate, at least in part, HIV expression in brain. Pre-existing IL-1 was found to be dramatically increased whereas TGF-Beta was induced in tissues from HIV-infected compared to seronegative individuals without neuropathology or brain disease. The HIV infected individuals whose brains were assayed displayed a broad range of neurological abnormalities characteristic of AIDS. All tissues from HIV-infected individuals displayed reactive astrocytosis but contained no perivascular infiltrates nor detectable HIV antigens (except in one case). Both cytokines were expressed by astrocytes and TGF-Beta was also expressed by microglia. IL-1 was also present in blood vessel endothelium whereas TGF-Beta was not. These results are consistant with those obtained in vitro and suggest that cytokines may be involved in the neuropathogenesis of HIV infection. However, the expression of these cytokines is not unique to HIV infection. The changes in the levels of IL-1 and TGF-Beta observed in AIDS brain were also observed in brains from patients with fever and several other disorders. These results suggest that these cytokines may be common mediators of the brains response to virus and other pathogenic insults rather than being specific to HIV infection. Nevertheless since cytokines such as TGF-Beta alter HIV expression in monocytic cells, they may at least in part determine the level of HIV expression in brain. We have demonstrated that murine brain cultures can become infected with a mixture of murine leukemia viruses known to cause immunodeficiency syndrome in mice. The data obtained in vivo and in vitro suggest that both microglia and astrocytes become infected. The data indicate that infected cells harbor a defective viral genome which has been previously demonstrated to be a critical component for disease induction. This animal model provides an opportunity for studying the molecular basis of retrovirus-mediated neuropathogenesis.

我们已经证明，人类星形胶质细胞和两个细胞系衍生 能够分泌已知能够 调节人类免疫缺陷病毒（HIV）表达：白细胞介素-6 （IL-6）、转化生长因子-β（TGF-β）和粒细胞 巨噬细胞集落刺激因子 这三种分泌物 细胞因子以时间和剂量依赖性方式被IL-1刺激。 发现IL-1刺激少突胶质细胞分泌TGF-β， 小胶质细胞 这些结果表明，细胞因子的分泌， 神经胶质细胞可能至少部分刺激脑中的HIV表达。 发现预先存在的IL-1显著增加，而 TGF-β在HIV感染的组织中诱导， 无神经病理学或脑部疾病的血清阴性个体。 的 艾滋病毒感染者的大脑被检测显示出广泛的 一系列艾滋病特有的神经异常 所有组织 HIV感染者显示反应性星形细胞增多， 没有血管周围浸润，也没有可检测到的HIV抗原 （除了一个例外）。 两种细胞因子均由星形胶质细胞表达， 小胶质细胞也表达TGF-β。 IL-1也存在于 而TGF-β则没有。 这些结果 与体外获得的结果一致，表明细胞因子可能 参与HIV感染的神经发病机制。 但 这些细胞因子的表达不是HIV感染所独有的。 的 在AIDS脑中观察到的IL-1和TGF-β水平的变化， 在发烧和其他几种疾病患者的大脑中也观察到了这种现象。 紊乱 这些结果表明，这些细胞因子可能是常见的 脑对病毒和其他致病性损伤反应的介质 而不是针对HIV感染。 然而，自 细胞因子如TGF-β改变单核细胞中的HIV表达， 可能至少部分决定了HIV在大脑中的表达水平。 我们 已经证明，小鼠脑培养物可以感染一种 已知引起免疫缺陷的鼠白血病病毒的混合物 小鼠综合征 在体内和体外获得的数据表明， 小胶质细胞和星形胶质细胞都被感染。 数据表明 受感染的细胞携带有缺陷的病毒基因组， 被证明是诱发疾病的关键成分。 这 动物模型提供了一个机会，研究的分子基础， 逆转录病毒介导的神经发病机制。