INHIBITION OF HIV ACTIVATION BY SOLUBLE TUMOR NECROSIS FACTOR RECEPTOR

可溶性肿瘤坏死因子受体抑制 HIV 激活

• 批准号: 3792477
• 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/3792477
• 关键词: HIV infections; chimeric proteins; cytokine receptors; genetic transcription; human genetic material tag; human immunodeficiency virus 1; human tissue; nucleic acid repetitive sequence; receptor binding; tissue /cell culture; tumor necrosis factor alpha

The inflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), has been shown to stimulate HIV-1 replication in both chronically and acutely infected T-lymphocytes and monocytes. The activation of the HIV-Long Terminal Repeat (HIV-LTR) and subsequent increase in virus production is linked to TNF activation of the cellular transcription factor, NF-kB. We have 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 is a monomer containing the entire 234 residues of the extracellular (ligand-binding) portion of p80. A second form is a homodimer chimeric protein containing these same residues fused to a truncated human IgG(l) immunoglobulin chain, and thus resembles a bivalent antibody without light chains. These recombinant proteins were tested for their ability to inhibit TNF-alpha-induced expression of HIV-1 in chronically infected human cell lines as determined by viral reverse transcriptase activity. We also examined the ability of the soluble receptors to limit the activation of HIV-LTR transcription. The soluble TNF receptor dimer was most effective at blocking the TNF-alpha-induced expression in both monocytic and lymphocytic cell lines. The ratio of receptor to TNF-alpha was critical, with optimal inhibition requiring a 10-fold excess of receptor. Monomeric receptor was less effective at blocking and, at times, was capable of augmenting the activity of TNF-alpha. Thus, our data suggests that TNF-alpha-induced HIV-1 expression can be limited in vitro using a dimeric form of the TNF receptor at specific ratios in excess of TNF-alpha.

炎症细胞因子肿瘤坏死因子-α (TNF-α) 已被证明可以刺激 HIV-1 的长期和急性复制 感染的 T 淋巴细胞和单核细胞。 HIV-Long 的激活 末端重复（HIV-LTR）和随后病毒产量的增加是 与细胞转录因子 NF-kB 的 TNF 激活有关。 我们 测试了两种形式的可溶性重组 1 型 (p80) 的能力 TNF 受体可在体外抑制 TNF 诱导的 HIV 激活。 一种形式是 该受体是一个包含完整234个残基的单体 p80 的细胞外（配体结合）部分。 第二种形式是 含有这些相同残基的同源二聚体嵌合蛋白融合到 截短的人 IgG(l) 免疫球蛋白链，因此类似于 不含轻链的二价抗体。 这些重组蛋白是 测试其抑制 TNF-α 诱导的 HIV-1 表达的能力 通过病毒逆转确定慢性感染的人类细胞系 转录酶活性。 我们还检查了可溶性的能力 受体来限制 HIV-LTR 转录的激活。 可溶性 TNF 受体二聚体在阻断 TNF-α 诱导的 在单核细胞和淋巴细胞系中表达。 的比例为 TNF-α 受体至关重要，最佳抑制需要 受体过量10倍。 单体受体的效率较低 阻止并且有时能够增强 TNF-α。 因此，我们的数据表明 TNF-α 诱导的 HIV-1 使用 TNF 的二聚体形式可以在体外限制表达 受体以特定比例超过 TNF-α。