A platelet-activating factor antagonist, RP 55778, inhibits cytokine-dependent induction of human immunodeficiency virus expression in chronically infected promonocytic cells.

A platelet-activating factor antagonist, RP 55778, potently suppressed the induction of human immunodeficiency virus (HIV) expression in chronically infected promonocytic U1 cells. RP 55778 inhibited the production of reverse transcriptase activity in U1 cells stimulated with the transcriptionally active inducers of virus production, tumor necrosis factor alpha and phorbol 12-myristate 13-acetate. This effect was correlated only in part with a reduction in the levels of HIV RNA, suggesting that this agent was also affecting posttranscriptional levels of virus production. In this regard, RP 55778 effectively blocked the induction of HIV expression in U1 cells stimulated with interleukin 6 and granulocyte-macrophage colony-stimulating factor, which act predominantly as posttranscriptional activators of HIV expression. Finally, RP 55778 inhibited the production of endogenous tumor necrosis factor alpha in phorbol 12-myristate 13-acetate-stimulated cells, thereby interfering with an autocrine pathway of virus expression. The suppressive effects of RP 55778 on HIV expression appeared to be independent of the platelet-activating factor cell surface receptor on U1 cells. RP 55778 inhibited acute HIV replication in primary T-cell blasts and the proliferative capacity of these cells. This study suggests that RP 55778 may represent potentially useful compounds in the treatment of HIV infection. IMAGES:

血小板活化因子（platelet-activating factor）拮抗剂RP 55778可强效抑制慢性感染原单核细胞U1细胞中人类免疫缺陷病毒（HIV）表达的诱导过程。RP 55778可抑制经病毒生产转录激活诱导剂——肿瘤坏死因子α（tumor necrosis factor alpha）与佛波醇12-肉豆蔻酸酯13-乙酸酯（phorbol 12-myristate 13-acetate）——刺激的U1细胞内逆转录酶活性的产生。该效应仅部分与HIV RNA水平降低相关，提示该化合物还可影响病毒生产的转录后调控过程。在此方面，RP 55778可有效阻断经白细胞介素6（interleukin 6）与粒细胞-巨噬细胞集落刺激因子（granulocyte-macrophage colony-stimulating factor）刺激的U1细胞内HIV表达的诱导，而这两种因子主要作为HIV表达的转录后激活因子发挥作用。最终，RP 55778可抑制佛波醇12-肉豆蔻酸酯13-乙酸酯刺激细胞中内源性肿瘤坏死因子α的产生，从而干扰病毒表达的自分泌通路。RP 55778对HIV表达的抑制效应似乎不依赖于U1细胞表面的血小板活化因子受体。RP 55778还可抑制原代T细胞母细胞中的急性HIV复制以及这些细胞的增殖能力。本研究表明，RP 55778或可成为治疗HIV感染的潜在有效化合物。IMAGES: