Human immunodeficiency virus type 1 infection induces cyclin T1 expression in macrophages
Human immunodeficiency virus type 1 infection induces cyclin T1 expression in macrophages
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DOI：
10.1128/jvi.78.15.8114-8119.2004
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发表时间：
2004-08-01
影响因子：
5.4
通讯作者：
Rice, AP
中科院分区：
文献类型：
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作者：
Liou, LY;Herrmann, CH;Rice, AP
人免疫缺陷病毒1型（HIV-1）的达特蛋白对于病毒复制是必需的，并且通过与由Cdk 9和细胞周期蛋白T1组成的细胞蛋白激酶结合来激活RNA聚合酶R转录延伸。达特通过与细胞周期蛋白T1的直接蛋白质-蛋白质相互作用与该激酶复合物结合。单核细胞/巨噬细胞是HIV-1感染的重要靶点，以前的工作表明，在从血液中分离的单核细胞中，细胞周期蛋白T1而不是Cdk 9蛋白表达较低。虽然Cdk 9表达在体外单核细胞分化为巨噬细胞期间以高水平表达，但细胞周期蛋白T1表达在分化的最初几天期间被诱导，并在1至2周后被关闭。我们在这里表明，关闭细胞周期蛋白T1的表达在晚分化的巨噬细胞涉及蛋白酶体介导的蛋白水解。我们还表明，细胞周期蛋白T1可以被一些病原体相关的分子模式，激活巨噬细胞，表明细胞周期蛋白T1的上调是先天免疫反应的一部分。此外，我们发现，HIV-1感染早期的巨噬细胞分化的结果在持续的细胞周期蛋白T1的表达，而感染晚期分化的结果在再诱导细胞周期蛋白T1。从腺病毒载体表达病毒Nef蛋白表明，Nef有助于HIV-1诱导细胞周期蛋白T1。这些发现表明，HIV-1感染劫持了巨噬细胞中先天免疫反应的一个组成部分，导致病毒复制的增强而不是抑制。
The Tat protein of human immunodeficiency virus type 1 (HIV-1) is essential for viral replication and activates RNA polymerase R transcriptional elongation through the association with a cellular protein kinase composed of Cdk9 and cyclin T1. Tat binds to this kinase complex through a direct protein-protein interaction with cyclin T1. Monocytes/macrophages are important targets of HIV-1 infection, and previous work has shown that cyclin T1 but not Cdk9 protein expression is low in monocytes isolated from blood. While Cdk9 expression is expressed at a high level during monocyte differentiation to macrophages in vitro, cyclin T1 expression is induced during the first few days of differentiation and is shut off after 1 to 2 weeks. We show here that the shutoff of cyclin T1 expression in late-differentiated macrophages involves proteasome-mediated proteollysis. We also show that cyclin T1 can be reinduced by a number of pathogen-associated molecular patterns that activate macrophages, indicating that up-regulation of cyclin T1 is part of an innate immune response. Furthermore, we found that HIV-1 infection early in macrophage differentiation results in sustained cyclin T1 expression, while infection at late times in differentiation results in the reinduction of cyclin T1. Expression of the viral Nef protein from an adenovirus vector suggests that Nef contributes to the HIV-1 induction of cyclin T1. These findings suggest that HIV-1 infection hijacks a component of the innate immune response in macrophages that results in enhancement rather than inhibition of viral replication.