REGULATION OF CYTOKINE EXPRESSION BY HIV

巨噬细胞(MOS)在HIV的发病机制中起关键作用 感染，既是病毒复制的目标，也是 多功能细胞因子。我们之前曾报道过1)HIV-1 包膜糖蛋白gp120刺激分泌有效的 人巨噬细胞产生的血管收缩多肽--内皮素-1 一种浓度依赖的方式，2)循环单核细胞 HIV感染者表达ET-1基因，而健康人的细胞 对照组没有，3)和脑巨噬细胞的患者 HIV脑病患者ET-1均为阳性。因此，单核细胞来源的ET-1 似乎是在艾滋病毒感染期间受到刺激，并具有强大的血管活性 属性可能会潜在地调节大脑中的变化 血流灌注模式与艾滋病痴呆综合征相关。我们的研究 看HIV感染对机体和机体的影响 人巨噬细胞刺激产生ET-1提示感染 嗜巨噬细胞HIV-1分离株不诱导ET-1分泌 通过一种已知的诱导剂--脂多糖来增强其产量。这一分析是 扩大到包括嗜神经性艾滋病毒分离株，这些分离株也是 巨噬细胞嗜性。此外，从HIV感染者和 在感染后的不同时间对未感染的MO进行检查 应用RT-PCR技术检测ET-1和/或 一氧化氮合酶(NOS)，一种负责产生 有效的血管扩张剂，NO，被表达。为了进一步澄清 HIV相关认知/运动复合体的发病机制，我们研究了 HIV感染巨噬细胞培养上清液的神经毒性及其关系 HIV感染的Mos和星形胶质细胞之间的关系。我们的初步数据使用 人类神经元(NT2)和神经母细胞瘤(SK-M-NC)细胞提示 感染HIV的MOS的培养上清液对 分化的神经元。相比之下，感染艾滋病毒的MOS在 体外培养的U373人脑星形细胞瘤细胞引起多个脱细胞区域 出现在细胞单层中，而未感染的MOS没有有害的 效果。后一种发现与病理结果相一致。 在体内观察到的变化，其中HIV感染的MO被 大脑中的局灶性稀疏。有趣的是，U373的存在 星形细胞抑制了MOS中HIV的复制，这表明 如果HIV在大脑中存在，星形胶质细胞可能会抑制这种传播 活着。研究正在进行中，以确定在 星形胶质细胞的研究是由细胞或病毒衍生的可溶性 因素，如果是这样的话，确定来源和身份。

Macrophages (MOs) play a critical role in the pathogenesis of HIV infection, both as targets for viral replication and as sources of multifunctional cytokines. We have previously reported that 1) the HIV-1 envelope glycoprotein, gp120, stimulates secretion of the potent vasoconstrictive peptide, endothelin-1 (ET-1), from human macrophages in a concentration-dependent manner, 2) that circulating monocytes in HIV-infected individuals express the ET-1 gene, while cells from healthy controls do not, 3) and that cerebral macrophages in patients with HIV-encephalopathy are positive for ET-1. Thus, monocyte-derived ET-1 appears to be stimulated during HIV infection and the potent vasoactive properties could potentially mediate alterations in the cerebral perfusion pattern associated with AIDS dementia complex. Our studies looking at the effect of HIV infection on both constitutive and stimulated production of ET-1 by human MOs suggest that infection with macrophage tropic HIV-1 isolates neither induces secretion of ET-1 nor potentiates its production by a known inducer, LPS. This analysis is being expanded to include neurotropic HIV isolates that are also macrophage tropic. In addition, mRNA prepared from HIV-infected and uninfected MOs at various times following infection are being examined using RT-PCR techniques to determine whether the genes for ET-1 and/or nitric oxide synthase (NOS), an enzyme responsible for production of the potent vasodilator, NO, are expressed. To further clarify the pathogenesis of HIV-associated cognitive/motor complex, we examined the neurotoxicity of supernatants from HIV-infected MOs and the relationship between HIV-infected MOs and astrocytes. Our preliminary data using human neuronal (NT2) and neuroblastoma (SK-M-NC) cells suggest that supernatants from HIV-infected MOs are not directly toxic to differentiated neurons. In contrast, HIV-infected MOs co-cultured in vitro with U373 human astrocytoma cells caused multiple acellular areas to appear in the cell monolayers, while uninfected MOs had no detrimental effects. These latter findings are consistent with the pathologic changes observed in vivo, in which HIV-infected MOs are surrounded by focal rarefaction in the brain. Intriguingly, the presence of U373 astrocytic cells suppressed HIV replication in MOs, suggesting that astrocytes could potentially inhibit the spread if HIV in the brain in vivo. Studies are ongoing to ascertain whether the effects observed in the astrocyte studies are mediated by cellular- or viral-derived soluble factors and, if so, to determine both the source and identity.