MODULATION OF HIV-1 REPLICATION BY CYTOKINES AND SOLUBLE CYTOKINE RECEPTORS

细胞因子和可溶性细胞因子受体对 HIV-1 复制的调节

• 批准号: 5200743
• 负责人: K 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/5200743
• 关键词: T lymphocyte; cytokine; cytokine receptors; gene induction /repression; human immunodeficiency virus 1; human tissue; interleukin 4; monocyte; tissue /cell culture; transcription factor; tumor necrosis factor alpha; virus replication

We have previously shown that the inflammatory cytokine, tumor necrosis factor-a (TNF-a), can stimulate human immunodeficiency virus type 1(HIV-1) replication in chronically and acutely infected T lymphocytic and monocytic cell lines. This activation is linked to TNF activation of the cellular transcription factor, NF-kB. We subsequently reported that a soluble, dimeric form of the 80 kD TNF receptor (FcTNFR) could effectively block TNF-mediated induction of HIV-1 expression in both monocytic and lymphocytic cell lines. The ratio of receptor to TNF was critical, with optimal inhibition requiring a five-fold molar excess of FcTNFR. The cytokine, interleukin-4 (IL-4) has been reported to both enhance and inhibit replication of HIV-1 in human monocytes in vitro, depending on the state of cellular differentiation. We have recently tested a purified form of soluble human IL-4 receptor (sIL-4R) for their ability to modulate the effects of IL-4 on HIV-infected, monocyte-derived macrophages. We find that IL-4, when present throughout infection, inhibits HIV-1 replication in human macrophages. In contrast, IL-4 added at later times during the course of infection enhanced HIV replication. We also found that sIL4R, when used at low ratios with respect to the IL-4 concentration, increased the IL-4 mediated inhibition of virus replication in differentiated macrophages. However, when sIL-4R were present in 100-fold excess of IL-4, the inhibitory effects of the cytokine were reversed. These results suggest that sIL-4R can augment the biological effects of IL-4 when used at concentrations equivalent to IL-4, but at a high molar excess they function as an antagonist. Similar results were observed in preliminary experiments using an antibody specific for IL-4. These results provide some insight into the complex nature of cytokine/cytokine receptor networks that may exist in vivo, and the potential complications that may result from therapeutic use of soluble cytokine receptors.

我们以前已经证明，炎症细胞因子，肿瘤坏死， 因子-a（TNF-α），可刺激人类免疫缺陷病毒型 1（HIV-1）在慢性和急性感染的T淋巴细胞中的复制 和单核细胞系。 这种激活与TNF激活有关 细胞转录因子NF-κ B的表达。 我们随后报告说， 80 kD TNF受体（FcTNFR）的可溶性二聚体形式可以 有效地阻断TNF介导HIV-1表达的诱导， 单核细胞和淋巴细胞细胞系。 受体与TNF的比值为 关键，最佳抑制需要5倍摩尔过量的 FcTNFR。 据报道，细胞因子白细胞介素-4（IL-4）既能增强， 体外抑制HIV-1在人单核细胞中的复制， 细胞分化的状态。 我们最近测试了一个 纯化形式的可溶性人IL-4受体（sIL-4 R）， 调节IL-4对HIV感染的单核细胞源性 巨噬细胞 我们发现IL-4，当在整个感染过程中存在时， 抑制HIV-1在人类巨噬细胞中的复制。相反，IL-4添加 在感染过程的后期增强了艾滋病毒的复制。 我们还发现，当相对于对照组以低比例使用时， IL-4浓度增加，IL-4介导的病毒抑制作用增强 在分化的巨噬细胞中复制。 但是，当sIL-4 R 存在于100倍过量的IL-4中， 细胞因子逆转。 这些结果表明，sIL-4 R可以增加 IL-4的生物效应，当使用浓度相当于 IL-4，但在高摩尔过量时，它们起拮抗剂的作用。 类似 在使用抗体的初步实验中观察到结果 对IL-4特异。 这些结果提供了一些洞察复杂的 可能存在于体内的细胞因子/细胞因子受体网络的性质，以及 治疗性使用可能导致的潜在并发症 可溶性细胞因子受体