Prostratin: activation of latent HIV-1 expression suggests a potential inductive adjuvant therapy for HAART
Prostratin: activation of latent HIV-1 expression suggests a potential inductive adjuvant therapy for HAART
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DOI：
10.1182/blood.v98.10.3006
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发表时间：
2001-11-15
期刊：
影响因子：
20.3
通讯作者：
Pomerantz, RJ
中科院分区：
文献类型：
--
作者：
Kulkosky, J;Culnan, DM;Pomerantz, RJ
Prostratin是一种独特的佛波醇酯，刺激蛋白激酶C活性，但不促进肿瘤。值得注意的是，prostratin也能够抑制从头人类免疫缺陷病毒1型（HIV-1）感染，但上调潜伏前病毒的病毒表达。Prostratin缺乏肿瘤促进作用，加上其阻断病毒传播但诱导潜伏前病毒表达的能力，促使研究确定这种化合物是否可以作为高活性抗逆转录病毒治疗（HAART）患者的诱导辅助治疗。目前的实验表明，prostratin是一种有效的单核吞噬细胞的有丝分裂原，具有佛波醇肉豆蔻酸酯醋酸酯（PMA）的许多活动，具有显着的功能差异。Prostratin与PMA一样，加速骨髓细胞系HL-60和THP-1以及来自骨髓和外周血的单核吞噬细胞的分化。酶联免疫吸附测定和基因阵列分析表明，在用prostratin处理细胞后，蛋白质和信使RNA的表达发生了显著变化，这与吞噬细胞的活化和分化一致。Prostratin阻断HIV-1感染与下调CD 4受体表达有关。阵列分析表明HIV-1辅助受体CXCR 4和CCR 5的类似下调，这也可能降低经处理的宿主细胞的病毒感染性。最后，prostratin能够上调接受HAART的患者的CD 8（+）T淋巴细胞耗尽的外周血单核细胞的HIV-1表达。这一新的观察结果表明，该药物可能是一个很好的候选人，以加强HAART诱导表达潜伏的HIV-1的最终目标是消除持久的病毒水库在某些个人感染HIV-1。(C)2001年，美国血液学会。
Prostratin is a unique phorbol ester that stimulates protein kinase C activity but is nontumor promoting. Remarkably, prostratin is also able to inhibit de novo human immunodeficiency virus type 1 (HIV-1) infection yet up-regulate viral expression from latent proviruses. Prostratin's lack of tumor promotion, coupled with its ability to block viral spread yet induce latent proviral expression, prompted studies to determine whether this compound could serve as an inductive adjuvant therapy for patients treated with highly active antiretroviral therapy (HAART). The current experiments indicate that prostratin is a potent mitogen for mononuclear phagocytes possessing many of the activities of phorbol myristate acetate (PMA) with notable functional differences. Prostratin, like PMA, accelerates differentiation of the myeloid cell-lines, HL-60 and THP-1, as well as mononuclear phagocytes from bone marrow and peripheral blood. Enzyme-linked Immunosorbent assay and gene array analyses indicate significant changes in the expression of proteins and messenger RNA after treatment of cells with prostratin, consistent with phagocyte activation and differentiation. Prostratin blocks HIV-1 infection relating to down-regulation of CD4 receptor expression. The array analysis indicates a similar down-regulation of the HIV-1 coreceptors, CXCR4 and CCR5, and this may also reduce viral infectivity of treated host cells. Finally, prostratin is capable of up-regulating HIV-1 expression from CD8(+) T lymphocyte-depleted peripheral blood mononuclear cells of patients undergoing HAART. This novel observation suggests the agent may be an excellent candidate to augment HAART by inducing expression of latent HIV-1 with the ultimate goal of eliminating persistent viral reservoirs in certain individuals infected with HIV-1. (C) 2001 by The American Society of Hematology.