Department of Dermatology and Wound Healing, Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, Wales, United Kingdom.
J Biol Chem. 2012 Jun 22;287(26):22015-29. doi: 10.1074/jbc.M111.319996. Epub 2012 Apr 6.
Influenza virus infections lead to a burst of type I interferon (IFN) in the human respiratory tract, which most probably accounts for a rapid control of the virus. Although in mice, IFN-induced Mx1 factor mediates a major part of this response, the situation is less clear in humans. Interestingly, a recently identified IFN-induced cellular protein, tetherin (also known as CD317, BST-2, or HM1.24), exerts potent antiviral activity against a broad range of retroviruses, as well as several other enveloped viruses, by impeding the release of newly generated viral particles from the cell surface. Here we show that influenza virus belongs to the targets of this potent antiviral factor. Ectopic expression of tetherin strongly inhibited fully replicative influenza virus. In addition, depleting endogenous tetherin increased viral production of influenza virions, both in cells constitutively expressing tetherin and upon its induction by IFN. We further demonstrate, by biochemical and morphological means, that tetherin exerts its antiviral action by tethering newly budded viral particles, a mechanism similar to the one that operates against HIV-1. In addition, we determined that the magnitude of tetherin antiviral activity is comparable with or higher than the one of several previously identified anti-influenza cellular factors, such as MxA, ADAR1, ISG15, and viperin. Finally, we demonstrate that influenza virus reduces the impact of tetherin-mediated restriction on its replication by several mechanisms. First, the influenza virus NS1 protein impedes IFN-mediated tetherin induction. Second, influenza infection leads to a decrease of tetherin steady state levels, and the neuraminidase surface protein partly counteracts its activity. Overall, our study helps to delineate the intricate molecular battle taking place between influenza virus and its host cells.
流感病毒感染会导致人体呼吸道中Ⅰ型干扰素（IFN）的爆发，这很可能是迅速控制病毒的原因。虽然在小鼠中，IFN 诱导的 Mx1 因子介导了这一反应的主要部分，但在人类中情况并不清楚。有趣的是，最近发现的一种 IFN 诱导的细胞蛋白， tetherin（也称为 CD317、BST-2 或 HM1.24），通过阻止新生成的病毒粒子从细胞表面释放，对广泛的逆转录病毒以及其他几种包膜病毒发挥强大的抗病毒活性。在这里，我们表明流感病毒是这种强大抗病毒因子的靶标。tetherin 的异位表达强烈抑制了完全复制的流感病毒。此外，耗尽内源性 tetherin 会增加流感病毒粒子的产生，无论是在细胞中持续表达 tetherin 还是在 IFN 诱导时。我们还通过生化和形态学手段进一步证明，tetherin 通过束缚新出现的病毒粒子来发挥其抗病毒作用，这种机制类似于针对 HIV-1 的作用机制。此外，我们确定 tetherin 的抗病毒活性的幅度与几种先前鉴定的抗流感细胞因子（如 MxA、ADAR1、ISG15 和 viperin）相当或更高。最后，我们证明流感病毒通过多种机制减轻了 tetherin 介导的对其复制的限制的影响。首先，流感病毒 NS1 蛋白阻碍了 IFN 介导的 tetherin 诱导。其次，流感感染导致 tetherin 稳定水平下降，而神经氨酸酶表面蛋白部分抵消了其活性。总的来说，我们的研究有助于描绘流感病毒与其宿主细胞之间发生的复杂分子战斗。
