ROLE OF CYTOKINES IN THE REGULATION OF HIV EXPRESSION

参与调节作用的细胞和分子途径 促炎和免疫调节细胞因子对人类 免疫缺陷病毒（HIV）的表达/复制进行了研究。 各种细胞因子之间的复杂相互作用，如白细胞介素 （IL）-10和肿瘤坏死因子（TNF）-α或IL-6之间，以及 细胞因子和其他细胞介导的信号，如细胞因子的诱导物， 在调节HIV表达方面， 在原发性单核细胞源性巨噬细胞（MDM）和/或 慢性感染的细胞系。 分子基础研究 这些影响表现出多种机制，包括 转录和转录后事件，其中细胞因子 影响艾滋病毒表达。 HIV的自分泌/旁分泌刺激 内源性细胞因子的表达在MDM和原发性 外周血单个核细胞 在这些系统中， 细胞因子分泌和/或生理试剂如IL-10的活性， 可溶性细胞因子受体或拮抗剂，或通过药理学试剂， 如喷替福林，显著抑制了HIV 复制的 还在猿猴中进行了体内试验， 免疫缺陷病毒（SIV）感染的猕猴动物模型。 虽然没有 观察到急性期相关TNF-α产生的抑制， 喷替茶碱治疗的动物表现出较低的血浆和细胞相关 病毒血症、淋巴结细胞凋亡减少和可能的延迟性疾病 进展 细胞介导的HIV调节的新机制 使用PBMC或淋巴结（LN）证实表达/复制 来自HIV感染个体的细胞或慢性感染细胞 线 发现IL-12允许从未分级分离的HIV PBMC或LN细胞在CD8介导的病毒抑制剂的存在下， 活性;初步数据表明IL-12可以干扰或绕过 CD8介导的抑制。 CD30分子的触发， 被描述为TNF-α受体家族的成员，被发现有效地 在慢性感染细胞中诱导HIV表达，最可能是通过 激活细胞转录因子NF-κ B。 这些研究 表明内源性细胞因子可能在其中发挥重要作用 HIV疾病的发病机制。 这些信息可能会证明有用， 治疗策略的设计。

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.