Human cyclin T1 expression ameliorates a T-cell-specific transcriptional limitation for HIV in transgenic rats, but is not sufficient for a spreading infection of prototypic R5 HIV-1 strains ex vivo
Human cyclin T1 expression ameliorates a T-cell-specific transcriptional limitation for HIV in transgenic rats, but is not sufficient for a spreading infection of prototypic R5 HIV-1 strains ex vivo
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DOI：
10.1186/1742-4690-6-2
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发表时间：
2009-01-13
期刊：
影响因子：
3.3
通讯作者：
Keppler, Oliver T.
中科院分区：
文献类型：
--
作者：
Michel, Nico;Goffinet, Christine;Keppler, Oliver T.
背景：来自原生啮齿类动物的细胞在HIV复制的不同步骤中存在限制。大鼠原代CD 4 T细胞，但不是巨噬细胞，表现出深刻的转录缺陷，改善了瞬时反式互补与人类Tat相互作用蛋白细胞周期蛋白T1（hCycT 1）。结果：在这里，我们产生的转基因大鼠，选择性表达hCycT 1在CD 4 T细胞和巨噬细胞。大鼠T细胞中hCycT 1的表达促进了早期HIV基因的表达，使其水平接近感染的原代人T细胞。hCycT 1的表达是必要的，但不足以增强来自个体转基因动物的T细胞中的HIV转录，表明内源性细胞因子是大鼠中HIV基因表达的关键共调节因子。来自hCD 4/hCCR 5/hCycT 1转基因大鼠的T细胞不支持原型野生型R5 HIV-1株的体外生产性感染，表明在这种主要啮齿动物细胞类型中复制周期的晚期存在一种或多种显著限制。值得注意的是，我们鉴定出了一种具有复制能力的HIV-1 GFP报告菌株（R7/3 YU-2 Env），该菌株在hCD 4/hCCR 5转基因大鼠的原代T细胞中表现出扩散性、主要是细胞间介导的感染特征。此外，这种重组HIV-1株的复制显着增强hCycT 1转基因。迄今为止，这种独特的复制能力的病毒决定因素是目前unknown.Conclusion：因此，hCycT 1的表达是有益的从头HIV感染的转基因大鼠模型，但需要额外的宿主或病毒的遗传操作，以实现充分的持久性。
Background: Cells derived from native rodents have limits at distinct steps of HIV replication. Rat primary CD4 T-cells, but not macrophages, display a profound transcriptional deficit that is ameliorated by transient trans-complementation with the human Tat-interacting protein Cyclin T1 (hCycT1).Results: Here, we generated transgenic rats that selectively express hCycT1 in CD4 T-cells and macrophages. hCycT1 expression in rat T-cells boosted early HIV gene expression to levels approaching those in infected primary human T-cells. hCycT1 expression was necessary, but not sufficient, to enhance HIV transcription in T-cells from individual transgenic animals, indicating that endogenous cellular factors are critical co-regulators of HIV gene expression in rats. T-cells from hCD4/hCCR5/hCycT1-transgenic rats did not support productive infection of prototypic wild-type R5 HIV-1 strains ex vivo, suggesting one or more significant limitation in the late phase of the replication cycle in this primary rodent cell type. Remarkably, we identify a replication-competent HIV-1 GFP reporter strain (R7/3 YU-2 Env) that displays characteristics of a spreading, primarily cell-to-cell-mediated infection in primary T-cells from hCD4/hCCR5-transgenic rats. Moreover, the replication of this recombinant HIV-1 strain was significantly enhanced by hCycT1 transgenesis. The viral determinants of this so far unique replicative ability are currently unknown.Conclusion: Thus, hCycT1 expression is beneficial to de novo HIV infection in a transgenic rat model, but additional genetic manipulations of the host or virus are required to achieve full permissivity.