NEUROIMMUNOLOGY AND NEUROPATHOGENESIS OF HIV INFECTION

我们已经证明了人类星形胶质细胞和两个细胞系 它们能够分泌已知能够 调节人类免疫缺陷病毒(HIV)的表达：白细胞介素6 白介素6、转化生长因子-β和粒细胞 巨噬细胞集落刺激因子。三者的分泌物 IL-1以时间和剂量依赖的方式刺激细胞因子。 IL-1可刺激少突胶质细胞分泌转化生长因子-β。 小胶质细胞。这些结果表明，细胞因子的分泌通过 神经胶质细胞可能至少部分刺激大脑中HIV的表达。 先前存在的IL-1被发现显著增加，而 在HIV感染者的组织中诱导转化生长因子-β与 无神经病理或脑部疾病的血清阴性个体。这个 对艾滋病毒感染者的大脑进行化验后，他们的大脑显示出广泛的 艾滋病所特有的一系列神经异常。所有组织 从HIV感染者身上表现出反应性星形细胞增多症 不含血管周围浸润物或可检测到的HIV抗原 (除一宗个案外)。这两种细胞因子均由星形胶质细胞和 小胶质细胞也表达转化生长因子-β。IL-1也存在于 血管内皮细胞，而转化生长因子-β不是。这些结果是 与体外获得的结果一致，并表明细胞因子可能 参与HIV感染的神经发病机制。然而， 这些细胞因子的表达并不是HIV感染所独有的。这个 观察艾滋病大鼠脑内IL-1和转化生长因子-β水平的变化 在发烧患者和其他几个人的大脑中也观察到了 精神错乱。这些结果表明，这些细胞因子可能是常见的。 大脑对病毒和其他病原性侮辱反应的介体 而不是专门针对艾滋病毒感染。然而，自从 转化生长因子-β等细胞因子改变单核细胞中艾滋病毒的表达，它们 可能至少在一定程度上决定艾滋病毒在大脑中的表达水平。我们 已经证明小鼠的脑培养物可以感染一种 已知可导致免疫缺陷的小鼠白血病病毒混合物 小鼠的综合症。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会受到感染。数据表明， 被感染的细胞携带有缺陷的病毒基因组，而以前 被证明是诱发疾病的关键成分。这 动物模型为研究脑出血的分子基础提供了机会。 逆转录病毒介导的神经发病机制。

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.