REGULATION OF CYTOKINE EXPRESSION BY HIV

HIV 对细胞因子表达的调节

• 批准号: 2568960
• 负责人: K. A CLOUSE-STREBEL
• 金额: --
• 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/2568960
• 关键词: AIDS dementia complex; HIV envelope protein gp120; astrocytes; cytokine; endothelin; gene induction /repression; human immunodeficiency virus 1; human tissue; interferon gamma; lipopolysaccharides; macrophage; monocyte; neurotoxicology; nitric oxide; nitric oxide synthase; polymerase chain reaction; tissue /cell culture; vasoconstrictors

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.

巨噬细胞（MOs）在HIV的发病机制中起着关键作用 感染，既作为病毒复制的目标，又作为 多功能细胞因子。 我们以前曾报道过1）HIV-1 囊膜糖蛋白gp120，刺激分泌的强效 血管收缩肽，内皮素-1（ET-1），来自人巨噬细胞， 浓度依赖性方式，2）循环中的单核细胞 HIV感染者表达ET-1基因，而健康人的细胞表达ET-1基因。 对照组没有，3）和脑巨噬细胞在患者 HIV脑病患者ET-1阳性。 因此，单核细胞衍生的ET-1 似乎在HIV感染期间受到刺激， 这些特性可能会介导大脑中的改变， 与艾滋病痴呆综合征相关的脑灌注模式。 我们的研究 研究HIV感染对组织结构和 人MOs刺激ET-1产生表明感染 嗜巨噬细胞的HIV-1分离物既不诱导ET-1的分泌， 通过已知的诱导剂LPS增强其产生。 这种分析是 正在扩大到包括嗜神经性HIV分离株， 嗜巨噬细胞的 此外，从HIV感染者和 正在对感染后不同时间未感染的MO进行检查 使用RT-PCR技术来确定ET-1和/或ET-2的基因是否被激活。 一氧化氮合酶（NOS），一种负责产生 有效的血管扩张剂NO表达。 进一步明确 HIV相关的认知/运动复合体的发病机制，我们检查了 HIV感染的MOs上清液的神经毒性及其关系 感染艾滋病的MO和星形胶质细胞之间的联系 我们的初步数据使用 人神经元（NT 2）和神经母细胞瘤（SK-M-NC）细胞表明， 来自HIV感染的MO的上清液对 分化的神经元 与此相反，HIV感染的MOs共培养在 体外培养U373人星形细胞瘤细胞引起多个无细胞区 出现在细胞单层中，而未感染的MO没有有害的 方面的影响. 后一种结果与病理结果一致。 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 星形胶质细胞抑制HIV在MO中的复制，这表明 星形胶质细胞可以潜在地抑制艾滋病毒在大脑中的传播， vivo. 目前正在进行研究，以确定是否观察到的影响， 星形胶质细胞研究是由细胞或病毒来源的可溶性 如果是，则确定来源和身份。