Perno C F, Cooney D A, Gao W Y, Hao Z, Johns D G, Foli A, Hartman N R, Caliò R, Broder S, Yarchoan R
Medicine Branch, National Cancer Institute, Bethesda, MD 20892.
Blood. 1992 Aug 15;80(4):995-1003.
Cells of the monocyte lineage are important targets for the replication of human immunodeficiency virus (HIV). Our group and others have previously shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates HIV replication in monocyte/macrophages, but that it also enhances the anti-HIV activity of 2',3'-dideoxy-3'-azidothymidine (AZT). In the present study, we have explored the effects of other bone marrow stimulatory cytokines on the replication of HIV and on the anti-HIV activity of certain dideoxynucleosides in human peripheral blood monocyte/macrophages (M/M). Like GM-CSF, macrophage CSF (M-CSF) enhanced HIV replication in M/M. In contrast, granulocyte CSF (G-CSF) and erythropoietin (Epo) had no such effects. The anti-HIV activity of zidovudine (AZT) was increased in M/M exposed to GM-CSF. In contrast, the anti-HIV activity of AZT was unchanged in M/M exposed to M-CSF, and the activities of 2',3'-dideoxycytidine (ddC) and 2',3'-dideoxyinosine (ddl) were unchanged or slightly diminished in M/M stimulated with GM-CSF or M-CSF. These differential activities of AZT and ddC were paralleled by differential effects of the cytokines on the anabolism of these drugs to their active 5'-triphosphate moieties. GM-CSF increased the levels of AZT-5'-triphosphate (at least in part through an increase in thymidine kinase activity) and overall induced an increase in the ratio of AZT-5'-triphosphate/thymidine-5'-triphosphate. In contrast, M-CSF-induced increases in AZT-5'-triphosphate were roughly matched by increases in thymidine-5'-triphosphate. Also, GM-CSF- or M-CSF-induced increases in the levels of ddC-5'-triphosphate were associated with parallel increases in the levels of deoxycytidine-5'-triphosphate (the physiologic nucleoside that competes at the level of reverse transcriptase), so that there was relatively little net change in the ddC-5'-triphosphate/deoxycytidine-5'-triphosphate ratio. Thus, bone marrow stimulatory cytokines may have a variety of effects on HIV replication and on the activity and metabolism of dideoxynucleosides in M/M.
单核细胞系的细胞是人类免疫缺陷病毒（HIV）复制的重要靶细胞。我们小组和其他研究团队先前已表明，粒细胞-巨噬细胞集落刺激因子（GM-CSF）可刺激HIV在单核细胞/巨噬细胞中复制，但它也能增强2'，3'-二脱氧-3'-叠氮胸苷（AZT）的抗HIV活性。在本研究中，我们探讨了其他骨髓刺激细胞因子对HIV复制以及对人外周血单核细胞/巨噬细胞（M/M）中某些双脱氧核苷抗HIV活性的影响。与GM-CSF一样，巨噬细胞集落刺激因子（M-CSF）增强了HIV在M/M中的复制。相反，粒细胞集落刺激因子（G-CSF）和促红细胞生成素（Epo）则没有这种作用。在暴露于GM-CSF的M/M中，齐多夫定（AZT）的抗HIV活性增强。相反，在暴露于M-CSF的M/M中，AZT的抗HIV活性未发生变化，并且在经GM-CSF或M-CSF刺激的M/M中，2'，3'-双脱氧胞苷（ddC）和2'，3'-双脱氧肌苷（ddI）的活性未发生变化或略有降低。AZT和ddC的这些不同活性与细胞因子对这些药物合成其活性5'-三磷酸部分的代谢作用的不同影响相平行。GM-CSF增加了AZT-5'-三磷酸的水平（至少部分是通过胸苷激酶活性的增加），并总体上导致AZT-5'-三磷酸/胸苷-5'-三磷酸的比率升高。相反，M-CSF诱导的AZT-5'-三磷酸增加与胸苷-5'-三磷酸的增加大致相当。此外，GM-CSF或M-CSF诱导的ddC-5'-三磷酸水平升高与脱氧胞苷-5'-三磷酸（在逆转录酶水平竞争的生理性核苷）水平的平行升高相关，因此ddC-5'-三磷酸/脱氧胞苷-5'-三磷酸的比率相对变化较小。因此，骨髓刺激细胞因子可能对HIV复制以及M/M中双脱氧核苷的活性和代谢具有多种影响。
