INHIBITION OF HIV ACTIVATION BY SOLUBLE TUMOR NECROSIS FACTOR RECEPTOR

炎症细胞因子肿瘤坏死因子-α(TNF-α)具有 已被证明在慢性和急性地刺激HIV-1的复制 感染的T淋巴细胞和单核细胞。激活HIV-Long 末端重复序列(HIV-LTR)和随后病毒产量的增加是 与肿瘤坏死因子激活细胞转录因子-kB有关。我们 检测了两种形式的可溶性重组1型(P80)的能力 肿瘤坏死因子受体在体外抑制肿瘤坏死因子诱导的HIV激活。一种形式的 该受体是一种包含全部234个残基的单体。 P80的胞外(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成 截短的人免疫球蛋白(L)链，因此类似于 不含轻链的二价抗体。这些重组蛋白是 测试其抑制肿瘤坏死因子-α诱导的HIV-1表达的能力 通过病毒逆转试验确定的慢性感染的人类细胞系 转录酶活性。我们还检测了可溶性蛋白质的能力。 受体限制HIV-LTR转录的激活。可溶的 肿瘤坏死因子受体二聚体对肿瘤坏死因子-α的阻断作用最强。 在单核细胞系和淋巴细胞系中均有表达。的比例 肿瘤坏死因子-α的受体是关键的，最佳的抑制需要 受体过量10倍。单体受体在以下方面效果较差 阻断，并且有时能够增强 肿瘤坏死因子-α。因此，我们的数据表明，肿瘤坏死因子-α诱导的HIV-1 使用二聚体形式的肿瘤坏死因子可以在体外限制表达 受体的特定比例超过了肿瘤坏死因子-α。

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.