ROLE OF CYTOKINES IN THE REGULATION OF HIV EXPRESSION

细胞因子在 HIV 表达调节中的作用

• 批准号: 3746654
• 负责人: A KINTER
• 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/3746654
• 关键词: Macaca; biological signal transduction; cell differentiation; cytokine; cytokine receptors; gene expression; human immunodeficiency virus; human tissue; immunopathology; inhibitor /antagonist; interleukin 6; macrophage; monocyte; simian AIDSs; simian immunodeficiency virus; tissue /cell culture; tumor necrosis factor alpha; vasodilators; virus genetics; virus replication

The cellular and molecular pathways involved in the regulatory effects of proinflammatory and immunoregulatory cytokines on human immunodeficiency virus (HIV) expression/replication were investigated. The complex interactions between various cytokines, such as interleukin (IL)-10 and tumor necrosis factor (TNF)-alpha or IL-6, and between cytokines and other cell-mediated signals, such as inducers of cellular differentiation, with regard to regulation of HIV expression were demonstrated in primary monocyte-derived macrophages (MDM) and/or in chronically infected cell lines. Investigation of the molecular basis for these effects demonstrated multiple mechanisms, including transcriptional and post-transcriptional events, whereby cellular factors influence HIV expression. Autocrine/paracrine stimulation of HIV expression by endogenous cytokines was demonstrated in MDM and primary peripheral blood mononuclear cells. In these systems, inhibition of cytokine secretion and/or activity by physiologic agents, such as IL-10, soluble cytokine receptors or antagonists, or by pharmacologic agents, such as pentoxifylline, resulted in significant suppression of HIV replication. Pentoxifylline was also tested in vivo in the simian immunodeficiency virus (SIV)-infected macaque animal model. Although no inhibition of acute phase-related TNF-` production was observed, pentoxifylline-treated animals exhibited lower plasma and cell-associated viremia, lower apoptosis in the lymph node, and possibly delayed disease progression. Novel mechanisms of cell-mediated regulation of HIV expression/replication were demonstrated using PBMC or lymph node (LN) cells from HIV-infected individuals or in chronically infected cell lines. IL-12 was found to allow isolation of HIV from unfractionated PBMC or LN cells in the presence of CD8-mediated viral suppressive activity; preliminary data suggest that IL-12 can interfere or bypass CD8-mediated suppression. Triggering of the CD30 molecule, a newly described member of the TNF-alpha receptor family, was found to potently induce HIV expression in chronically infected cells, most likely by activating the cellular transcription factor NF-kappaB. These studies indicate that endogenous cytokines may play a major role in the pathogenesis of HIV disease. Such information may prove useful in the design of therapeutic strategies.

参与调控作用的细胞和分子途径 促炎细胞因子和免疫调节细胞因子对人体的影响 观察免疫缺陷病毒(HIV)的表达/复制情况。 各种细胞因子之间的复杂相互作用，如白细胞介素2 (IL)-10和肿瘤坏死因子-α或IL-6之间 细胞因子和其他细胞介导的信号，如细胞因子的诱导物 在HIV表达调控方面的分化是 在原代单核细胞来源的巨噬细胞(MDM)和/或 慢性感染的细胞系。分子基础的研究 对于这些效应，展示了多种机制，包括 转录和转录后事件，其中细胞因子 影响HIV的表达。HIV的自分泌/旁分泌刺激 内源性细胞因子在MDM和原发肿瘤中的表达 外周血单核细胞。在这些系统中，抑制 细胞因子的分泌和/或生理因子的活性，如IL-10， 可溶性细胞因子受体或拮抗剂，或通过药物制剂， 如己酮可可碱，可显著抑制HIV 复制。己酮可可碱也在猿猴体内进行了测试 免疫缺陷病毒(SIV)感染猕猴动物模型。虽然不是 观察到急性时相相关肿瘤坏死因子-`的产生受到抑制。 己酮可可碱处理的动物表现出较低的血浆和细胞相关 病毒血症，淋巴组织细胞凋亡率降低，以及可能的延迟性疾病 进步。细胞介导的HIV调控新机制 使用PBMC或淋巴结(LN)显示表达/复制 来自HIV感染者或慢性感染细胞的细胞 台词。IL-12被发现可以将HIV从普通细胞中分离出来 CD8介导病毒抑制作用下的PBMC或LN细胞 活动；初步数据显示IL-12可以干扰或绕过 CD8介导的抑制作用。触发CD30分子，一种新的 被描述为肿瘤坏死因子-α受体家族的成员，被发现具有强大的 在慢性感染细胞中诱导HIV表达，很可能是通过 激活细胞转录因子核因子-kappaB。这些研究 提示内源性细胞因子可能在脑出血中起重要作用。 HIV疾病的发病机制。这些信息可能会被证明在 治疗策略的设计。