Kinoshita S, Chen B K, Kaneshima H, Nolan G P
Department of Molecular Pharmacology, Stanford University School of Medicine, California 94305, USA.
Cell. 1998 Nov 25;95(5):595-604. doi: 10.1016/s0092-8674(00)81630-x.
Post HIV-1 entry, productive HIV-1 infection of primary T cells requires overcoming several cellular blocks to provirus establishment and replication. Activation of unknown host intracellular events overcomes such inhibitory steps and is concomitant with HIV-1 replication. We show that the transcription factor NFATc was sufficient as a cellular factor to induce a highly permissive state for HIV-1 replication in primary CD4+ T cells. NFATc overcame a blockade at reverse transcription and permitted active HIV-1 replication. Pharmacologic blockade of endogenous NFAT activity by FK506 or CsA inhibited synthesis of reverse transcription and also potently blocked HIV-1 replication. T cells therefore can become competent for HIV-1 replication by control of regulated host factors such as the NFATc transcription factor. The host mechanisms regulated by such permissivity factors are potential targets for anti-HIV-1 therapy.
在HIV-1进入细胞后,原代T细胞发生有效的HIV-1感染需要克服几个细胞层面上对前病毒建立和复制的阻碍。未知宿主细胞内事件的激活克服了这些抑制步骤,并与HIV-1复制同时发生。我们发现转录因子NFATc作为一种细胞因子足以在原代CD4+ T细胞中诱导出对HIV-1复制高度允许的状态。NFATc克服了逆转录过程中的一个障碍,并允许HIV-1进行活跃复制。用FK506或环孢素A对内源性NFAT活性进行药理阻断会抑制逆转录的合成,也能有效阻断HIV-1复制。因此,T细胞可以通过控制如NFATc转录因子等受调控的宿主因子而具备HIV-1复制能力。受这种允许性因子调控的宿主机制是抗HIV-1治疗的潜在靶点。