Bhalla Nishank, Sun Chengqun, Metthew Lam L K, Gardner Christina L, Ryman Kate D, Klimstra William B
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, United States.
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, United States.
Virology. 2016 Sep;496:147-165. doi: 10.1016/j.virol.2016.06.005. Epub 2016 Jun 15.
Most previous studies of interferon-alpha/beta (IFN-α/β) response antagonism by alphaviruses have focused upon interruption of IFN-α/β induction and/or receptor signaling cascades. Infection of mice with Venezuelan equine encephalitis alphavirus (VEEV) or Sindbis virus (SINV) induces serum IFN-α/β, that elicits a systemic antiviral state in uninfected cells successfully controlling SINV but not VEEV replication. Furthermore, VEEV replication is more resistant than that of SINV to a pre-existing antiviral state in vitro. While host macromolecular shutoff is proposed as a major antagonist of IFN-α/β induction, the underlying mechanisms of alphavirus resistance to a pre-existing antiviral state are not fully defined, nor is the mechanism for the greater resistance of VEEV. Here, we have separated viral transcription and translation shutoff with multiple alphaviruses, identified the viral proteins that induce each activity, and demonstrated that VEEV nonstructural protein 2-induced translation shutoff is likely a critical factor in enhanced antiviral state resistance of this alphavirus.
此前大多数关于甲病毒对α/β干扰素（IFN-α/β）反应拮抗作用的研究都集中在IFN-α/β诱导和/或受体信号级联反应的中断上。用委内瑞拉马脑炎甲病毒（VEEV）或辛德毕斯病毒（SINV）感染小鼠会诱导血清IFN-α/β，这会在未感染的细胞中引发全身性抗病毒状态，从而成功控制SINV的复制，但无法控制VEEV的复制。此外，在体外VEEV的复制比SINV对预先存在的抗病毒状态更具抗性。虽然宿主大分子合成关闭被认为是IFN-α/β诱导的主要拮抗剂，但甲病毒对预先存在的抗病毒状态的抗性潜在机制尚未完全明确，VEEV具有更强抗性的机制也不清楚。在此，我们利用多种甲病毒分离了病毒转录和翻译关闭，鉴定了诱导每种活性的病毒蛋白，并证明VEEV非结构蛋白2诱导的翻译关闭可能是该甲病毒增强抗病毒状态抗性的关键因素。
