Kulkosky J, Culnan D M, Roman J, Dornadula G, Schnell M, Boyd M R, Pomerantz R J
Dorrance H. Hamilton Laboratories, Center for Human Virology, Division of Infectious Diseases, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Blood. 2001 Nov 15;98(10):3006-15. doi: 10.1182/blood.v98.10.3006.
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.
苔藓抑素是一种独特的佛波酯，它能刺激蛋白激酶C的活性，但不具有促肿瘤作用。值得注意的是，苔藓抑素还能够抑制1型人类免疫缺陷病毒（HIV-1）的新发感染，却能上调潜伏前病毒的病毒表达。苔藓抑素缺乏促肿瘤作用，再加上它能够阻断病毒传播并诱导潜伏前病毒表达，促使人们开展研究以确定这种化合物是否可以作为接受高效抗逆转录病毒疗法（HAART）治疗的患者的诱导辅助治疗药物。目前的实验表明，苔藓抑素是单核吞噬细胞的一种强效有丝分裂原，具有许多十四酰佛波醇乙酯（PMA）的活性，但也存在显著的功能差异。与PMA一样，苔藓抑素能加速髓系细胞系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芯片分析表明，用苔藓抑素处理细胞后蛋白质和信使RNA的表达发生了显著变化，这与吞噬细胞的激活和分化一致。苔藓抑素通过下调CD4受体表达来阻断HIV-1感染。芯片分析表明HIV-1共受体CXCR4和CCR5也有类似的下调，这也可能降低经处理的宿主细胞的病毒感染性。最后，苔藓抑素能够上调接受HAART治疗患者的CD8+T淋巴细胞耗竭的外周血单核细胞中的HIV-1表达。这一新颖的观察结果表明，该药物可能是通过诱导潜伏的HIV-1表达来增强HAART的极佳候选药物，最终目标是消除某些感染HIV-1个体中持续存在的病毒储存库。
