Center for Lung Biology, University of South Alabama School of Medicine, 307 N University Boulevard, Mobile, AL 36688, USA.
Gene Ther. 2010 Oct;17(10):1253-61. doi: 10.1038/gt.2010.80. Epub 2010 May 20.
Gamma-retroviruses are commonly used to deliver genes to cells. Previously, we demonstrated that the synthetic anti-glucocorticoid and anti-progestin agent, mifepristone, increased gamma-retroviral infection efficiency in different target cells, independent of viral titer. In this study, we examine how this occurs. We studied the effect of mifepristone on different steps of viral infection (viral entry, viral survival, viral DNA synthesis and retrovirus integration into the host genome) in three distinct retroviral backbones using different virus recognition receptors. We also tested the potential role of glucocorticoid and progesterone receptors in mediating mifepristone's ability to increase gamma-retroviral infectivity. We show that mifepristone increases gamma-retroviral infection efficiency by facilitating viral integration into the host genome and that this effect seems to be due to mifepristone's anti-glucocorticoid, but not its anti-progestin, activity. These results suggest that inhibition of the glucocorticoid receptor enhances retroviral integration into the host genome and indicates that cells may have a natural protection again retroviral infection that may be reduced by glucocorticoid receptor antagonists.
γ-逆转录病毒常用于将基因递送到细胞中。此前，我们证明了合成的抗糖皮质激素和抗孕激素药物米非司酮可增加不同靶细胞中γ-逆转录病毒的感染效率，而与病毒滴度无关。在这项研究中，我们研究了这种情况是如何发生的。我们研究了米非司酮对三种不同逆转录病毒骨架中不同病毒感染步骤（病毒进入、病毒存活、病毒 DNA 合成和逆转录病毒整合到宿主基因组）的影响，使用了不同的病毒识别受体。我们还测试了糖皮质激素和孕激素受体在介导米非司酮增加γ-逆转录病毒感染力中的潜在作用。我们表明，米非司酮通过促进病毒整合到宿主基因组中，从而增加γ-逆转录病毒的感染效率，并且这种作用似乎是由于米非司酮的抗糖皮质激素作用，而不是其抗孕激素作用。这些结果表明，抑制糖皮质激素受体可增强逆转录病毒整合到宿主基因组中，并表明细胞可能具有天然的抗逆转录病毒感染的保护机制，而这种保护机制可能会被糖皮质激素受体拮抗剂削弱。
