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: 3748181
• 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/3748181
• 关键词: T lymphocyte; chimeric proteins; cytokine receptors; dimer; gene expression; human immunodeficiency virus 1; human tissue; immunoglobulin G; immunoglobulin structure; inhibitor /antagonist; interleukin 4; monocyte; nucleic acid repetitive sequence; protein isoforms; recombinant proteins; reverse transcriptase inhibitors; 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 tested the ability of two forms of soluble recombinant type 1 (p80) TNF receptor to inhibit TNF-induced HIV activation in vitro. One form of the receptor was a monomer containing the entire 234 residues of the extracellular (ligand-binding) portion of p80 (M-TNFR); the second form was a homodimer chimeric protein containing these same residues fused to a truncated human IgG1 immunoglobulin chain (Fc-TNFR). The soluble TNF receptor dimer proved to be most effective at blocking the TNF- induced 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 Fc-TNFR. Lower ratios of Fc-TNFR either failed to inhibit or actually enhanced virus expression. All concentrations of M-TNFR tested appeared to enhance TNF-mediated HIV expression. These data were publiished in PNAS (USA), volume 90, pp. 2335-2339 (1993). Interleukin-4 (IL-4) has been reported to either enhance or inhibit replication of HIV-1 in human monocytes in vitro, depending on their state of differentiation. We are currently testing a purified form of soluble human IL-4 receptor (sIL-4R) for its ability to modulate these effects. Our results thus far reveal that sIL4R used at low ratios with respect to the IL-4 concentration increase the IL-4 mediated inhibition of virus replication in differentiated monocytes (macrophages). However, when sIL-4R was present in 100-fold excess of IL-4, the inhibitory effects of the cytokine are reversed. These results suggest that sIL-4R augments the biological effects of IL-4 when used at concentrations equivalent to IL-4, but at a high molar excess functions as an antagonist.

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。 我们随后测试了 两种形式的可溶性重组1型（p80）TNF受体的能力， 体外抑制TNF诱导HIV活化。 受体的一种形式 是一个单体，含有细胞外的全部234个残基， p80（配体结合）部分（M-TNFR）;第二种形式是p80（配体结合）部分。 同源二聚体嵌合蛋白，其含有这些相同的残基， 截短的人IgG1免疫球蛋白链（Fc-TNFR）。 可溶性tnf 受体二聚体被证明是最有效的阻断TNF诱导的 单核细胞和淋巴细胞系中的HIV-1表达。 之比 受体的TNF是至关重要的，最佳的抑制需要 Fc-TNFR摩尔过量五倍。 较低的Fc-TNFR比率或者失败 来抑制或增强病毒的表达。 所有浓度的 M-TNFR测试似乎增强TNF介导的HIV表达。 这些 数据发表在PNAS（USA），第90卷，pp. 2335 - 2339（1993）。 白细胞介素-4（IL-4）已被报道可增强或抑制 体外人单核细胞中HIV-1的复制，取决于其 分化的状态。 我们目前正在测试一种纯化的 可溶性人IL-4受体（sIL-4R）调节这些 方面的影响. 我们的研究结果表明，在低比例下使用的sIL 4R与 相对于IL-4浓度增加IL-4介导的抑制 病毒在分化的单核细胞（巨噬细胞）中复制。 然而，在这方面， 当sIL-4R以IL-4的100倍过量存在时， 细胞因子的作用被逆转。 提示sIL-4R与IL-10、IL-12、IL-14、IL-16、IL-18、IL-19 当以浓度使用时增强IL-4的生物效应 相当于IL-4，但在高摩尔过量时， 拮抗剂