Gnirß Kerstin, Zmora Pawel, Blazejewska Paulina, Winkler Michael, Lins Anika, Nehlmeier Inga, Gärtner Sabine, Moldenhauer Anna-Sophie, Hofmann-Winkler Heike, Wolff Thorsten, Schindler Michael, Pöhlmann Stefan
Infection Biology Unit, German Primate Center, Göttingen, Germany.
Division of Influenza Viruses and other Respiratory Viruses, Robert Koch Institute, Berlin, Germany.
J Virol. 2015 Sep;89(18):9178-88. doi: 10.1128/JVI.00615-15. Epub 2015 Jun 24.
The expression of the antiviral host cell factor tetherin is induced by interferon and can inhibit the release of enveloped viruses from infected cells. The Vpu protein of HIV-1 antagonizes the antiviral activity of tetherin, and tetherin antagonists with Vpu-like activity have been identified in other viruses. In contrast, it is incompletely understood whether tetherin inhibits influenza A virus (FLUAV) release and whether FLUAV encodes tetherin antagonists. Here, we show that release of several laboratory-adapted FLUAV strains and a seasonal FLUAV strain is inhibited by tetherin, while pandemic FLUAV A/Hamburg/4/2009 is resistant. Studies with a virus-like particle system and analysis of reassortant viruses provided evidence that the viral hemagglutinin (HA) is an important determinant of tetherin antagonism but requires the presence of its cognate neuraminidase (NA) to inhibit tetherin. Finally, tetherin antagonism by FLUAV was dependent on the virion context, since retrovirus release from tetherin-positive cells was not rescued, and correlated with an HA- and NA-dependent reduction in tetherin expression. In sum, our study identifies HA and NA proteins of certain pandemic FLUAV as tetherin antagonists, which has important implications for understanding FLUAV pathogenesis.
Influenza A virus (FLUAV) infection is responsible for substantial global morbidity and mortality, and understanding how the virus evades the immune defenses of the host may uncover novel targets for antiviral intervention. Tetherin is an antiviral effector molecule of the innate immune system which can contribute to control of viral invasion. However, it has been unclear whether FLUAV is inhibited by tetherin and whether these viruses encode tetherin-antagonizing proteins. Our observation that several pandemic FLUAV strains can counteract tetherin via their HA and NA proteins identifies these proteins as novel tetherin antagonists and indicates that HA/NA-dependent inactivation of innate defenses may contribute to the efficient spread of pandemic FLUAV.
抗病毒宿主细胞因子束缚素的表达由干扰素诱导，可抑制包膜病毒从感染细胞中释放。HIV-1的Vpu蛋白可拮抗束缚素的抗病毒活性，并且在其他病毒中也鉴定出了具有Vpu样活性的束缚素拮抗剂。相比之下，束缚素是否抑制甲型流感病毒（FLUAV）释放以及FLUAV是否编码束缚素拮抗剂尚不完全清楚。在此，我们表明，几种实验室适应的FLUAV毒株和一种季节性FLUAV毒株的释放受到束缚素的抑制，而大流行的FLUAV A/Hamburg/4/2009具有抗性。使用病毒样颗粒系统的研究和重组病毒分析提供了证据，表明病毒血凝素（HA）是束缚素拮抗作用的重要决定因素，但需要其同源神经氨酸酶（NA）的存在才能抑制束缚素。最后，FLUAV对束缚素的拮抗作用取决于病毒体环境，因为从束缚素阳性细胞中释放的逆转录病毒未得到拯救，并且与HA和NA依赖的束缚素表达降低相关。总之，我们的研究确定了某些大流行FLUAV的HA和NA蛋白为束缚素拮抗剂，这对于理解FLUAV发病机制具有重要意义。
甲型流感病毒（FLUAV）感染导致全球大量发病和死亡，了解该病毒如何逃避宿主的免疫防御可能会发现新的抗病毒干预靶点。束缚素是先天免疫系统的一种抗病毒效应分子，可有助于控制病毒入侵。然而，尚不清楚FLUAV是否受到束缚素的抑制以及这些病毒是否编码束缚素拮抗蛋白。我们观察到几种大流行FLUAV毒株可通过其HA和NA蛋白对抗束缚素，这确定了这些蛋白为新型束缚素拮抗剂，并表明HA/NA依赖的先天防御失活可能有助于大流行FLUAV的有效传播。
