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: 2568961
• 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/2568961
• 关键词: T lymphocyte; cytokine; cytokine receptors; gene induction /repression; human immunodeficiency virus 1; human tissue; interleukin 4; macrophage; monocyte; nuclear factor kappa beta; oxidative stress; selenium; tissue /cell culture; transcription factor; tumor necrosis factor alpha; virus replication

Our previous studies have shown that the cytokine, tumor necrosis factor-a (TNF), stimulates HIV-1 replication in chronically infected T lymphocytic and monocytic cell lines and that a soluble, dimeric form of the 80 kD TNF receptor (TNFR:Fc) could effectively block this induction. The ratio of receptor to TNF was critical, with optimal inhibition requiring a 5-fold molar excess of TNFR:Fc. The cytokine, interleukin-4 (IL-4), has been reported to both enhance and inhibit replication of HIV-1 in human monocytes/macrophages (MO) in vitro, depending on the state of cellular differentiation. We tested purified soluble human IL-4 receptors (sIL-4R) for their ability to modulate the effects of IL-4 on HIV-infected MO. We find that IL-4, when present throughout infection, inhibits HIV-1 replication in differentiated macrophages. In contrast, IL-4 added at later times during infection enhanced HIV replication. In addition, 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 100-fold in excess of IL-4, the inhibitory effects of the cytokine were reversed. These results suggest that sIL-4R can function as an agonist to 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. The comparative effects of human and murine soluble IL-4 receptors, as well as anti-IL-4 antibodies are currently under investigation. These results will provide more 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. TNF has been shown to stimulate HIV-1 replication in vitro via activation of the cellular transcription factor, NF-kB. Oxidative stress also induces HIV replication through activation of NF-kB, and this effect could be reduced by selenium supplementation. The trace element, selenium, is incorporated into proteins as the amino acid selenocysteine, is essential for a functional immune system, can inhibit the expression of some viruses, and has been suggested as a therapeutic supplement in HIV infection. Since TNF and oxidative stress induce HIV by the same mechanism, we evaluated the effect of Se on TNF-induced HIV. We find that TNF-mediated induction of HIV-1 expression in both chronically infected T lymphocytic and monocytic cells can be reduced by selenium supplementation. Although selenium failed to suppress acute HIV infection of primary human T lymphocytes and monocytes, it did reduce the enhancing effects of TNF on acute HIV infection of monocytes, but not T cells. Thus, selenium supplementation may have some benefit as a supportive therapy in HIV-infected patients but, alone, would be incapable of ablating the detrimental effects of TNF.

我们以前的研究表明，细胞因子，肿瘤坏死， 因子-a（TNF），刺激HIV-1在慢性感染T细胞中复制 淋巴细胞和单核细胞细胞系以及可溶性二聚体形式的 80 kD TNF受体（TNFR：Fc）可有效阻断这种诱导作用。 受体与TNF的比例是关键，具有最佳抑制作用 需要5倍摩尔过量的TNFR：Fc。细胞因子白细胞介素-4 据报道，IL-4可以增强和抑制 体外人单核细胞/巨噬细胞（MO）中的HIV-1，取决于 细胞分化的状态。 我们测试了纯化的可溶性人IL-4 受体（sIL-4 R）调节IL-4对 感染艾滋病的MO 我们发现IL-4，当在整个感染过程中存在时， 抑制HIV-1在分化的巨噬细胞中的复制。 与此相反， 在感染后期加入IL-4可增强HIV复制。 在 另外，当相对于IL-4以低比例使用时， 浓度，增加IL-4介导的病毒抑制 在分化的巨噬细胞中复制。 但是，当sIL-4 R 存在超过IL-4 100倍， 细胞因子逆转。 这些结果表明，sIL-4 R可以发挥作用， 作为一种激动剂，当用于 浓度相当于IL-4，但在高摩尔过量时， 作为一种拮抗剂。 人类和小鼠的比较效果 可溶性IL-4受体以及抗IL-4抗体目前 在研究中 这些结果将提供更多的洞察力， 细胞因子/细胞因子受体网络的复杂性质可能存在于 体内，以及治疗可能导致的潜在并发症 使用可溶性细胞因子受体。 TNF已被证明刺激HIV-1 通过激活细胞转录因子进行体外复制， NF-κ B 氧化应激也通过激活诱导HIV复制 NF-kB的这种作用可通过补硒来降低。 微量元素硒以氨基酸的形式结合到蛋白质中。 酸性硒代半胱氨酸是功能性免疫系统所必需的， 抑制某些病毒的表达，并被认为是一种 艾滋病毒感染的治疗补充剂。 由于TNF和氧化应激 通过相同的机制诱导HIV，我们评估了Se对 TNF诱导的HIV。 我们发现TNF介导的HIV-1表达诱导 在慢性感染的T淋巴细胞和单核细胞中， 减少硒的补充。 虽然硒未能 抑制原代人T淋巴细胞急性HIV感染， 单核细胞，它确实降低了TNF对急性HIV的增强作用， 单核细胞感染，而不是T细胞。 因此，补充硒 作为HIV感染者的支持性治疗， 但是，单独的，将无法消除的有害影响， 的tnf