Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic.
Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
J Virol. 2020 Jun 1;94(12). doi: 10.1128/JVI.00416-20.
Tetherin/BST-2 is an antiviral protein that blocks the release of enveloped viral particles by linking them to the membrane of producing cells. At first, BST-2 genes were described only in humans and other mammals. Recent work identified BST-2 orthologs in nonmammalian vertebrates, including birds. Here, we identify the BST-2 sequence in domestic chicken () for the first time and demonstrate its activity against avian sarcoma and leukosis virus (ASLV). We generated a BST-2 knockout in chicken cells and showed that BST-2 is a major determinant of an interferon-induced block of ASLV release. Ectopic expression of chicken BST-2 blocks the release of ASLV in chicken cells and of human immunodeficiency virus type 1 (HIV-1) in human cells. Using metabolic labeling and pulse-chase analysis of HIV-1 Gag proteins, we verified that chicken BST-2 blocks the virus at the release stage. Furthermore, we describe BST-2 orthologs in multiple avian species from 12 avian orders. Previously, some of these species were reported to lack BST-2, highlighting the difficulty of identifying sequences of this extremely variable gene. We analyzed BST-2 genes in the avian orders Galliformes and Passeriformes and showed that they evolve under positive selection. This indicates that avian BST-2 is involved in host-virus evolutionary arms races and suggests that BST-2 antagonists exist in some avian viruses. In summary, we show that chicken BST-2 has the potential to act as a restriction factor against ASLV. Characterizing the interaction of avian BST-2 with avian viruses is important in understanding innate antiviral defenses in birds. Birds are important hosts of viruses that have the potential to cause zoonotic infections in humans. However, only a few antiviral genes (called viral restriction factors) have been described in birds, mostly because birds lack counterparts of highly studied mammalian restriction factors. Tetherin/BST-2 is a restriction factor, originally described in humans, that blocks the release of newly formed virus particles from infected cells. Recent work identified BST-2 in nonmammalian vertebrate species, including birds. Here, we report the BST-2 sequence in domestic chicken and describe its antiviral activity against a prototypical avian retrovirus, avian sarcoma and leukosis virus (ASLV). We also identify BST-2 genes in multiple avian species and show that they evolve rapidly in birds, which is an important indication of their relevance for antiviral defense. Analysis of avian BST-2 genes will shed light on defense mechanisms against avian viral pathogens.
Tetherin/BST-2 是一种抗病毒蛋白，通过将包裹的病毒颗粒与产生细胞的膜连接，阻止它们的释放。最初，BST-2 基因仅在人类和其他哺乳动物中被描述。最近的研究在非哺乳动物脊椎动物中发现了 BST-2 的同源物，包括鸟类。在这里，我们首次在家禽鸡中鉴定了 BST-2 序列，并证明了它对禽肉瘤和白血病病毒（ASLV）的活性。我们在鸡细胞中产生了 BST-2 敲除，并表明 BST-2 是干扰素诱导的 ASLV 释放阻断的主要决定因素。鸡 BST-2 的异位表达阻止了鸡细胞中 ASLV 的释放和人免疫缺陷病毒 1（HIV-1）在人细胞中的释放。使用 HIV-1 Gag 蛋白的代谢标记和脉冲追踪分析，我们验证了鸡 BST-2 在病毒释放阶段起作用。此外，我们在 12 个鸟类目中的多个禽类物种中描述了 BST-2 的同源物。以前，一些这些物种被报道缺乏 BST-2，这突出了识别这个极其多变的基因序列的困难。我们分析了禽类目 Galliformes 和 Passeriformes 中的 BST-2 基因，并表明它们在正选择下进化。这表明禽 BST-2 参与了宿主-病毒的进化军备竞赛，并表明一些禽病毒中存在 BST-2 拮抗剂。总之，我们表明鸡 BST-2 有可能作为一种限制因子对抗 ASLV。描述禽 BST-2 与禽病毒的相互作用对于了解鸟类中的先天抗病毒防御很重要。鸟类是具有感染人类潜力的病毒的重要宿主。然而，在鸟类中只描述了少数抗病毒基因（称为病毒限制因子），这主要是因为鸟类缺乏高度研究的哺乳动物限制因子的对应物。Tetherin/BST-2 是一种最初在人类中描述的限制因子，它阻止新形成的病毒颗粒从受感染细胞中释放。最近的研究在非哺乳动物脊椎动物物种中发现了 BST-2，包括鸟类。在这里，我们报告了在家禽鸡中的 BST-2 序列，并描述了它对典型的禽逆转录病毒，禽肉瘤和白血病病毒（ASLV）的抗病毒活性。我们还在多个禽类物种中鉴定了 BST-2 基因，并表明它们在鸟类中快速进化，这是它们与抗病毒防御相关的重要指示。对禽 BST-2 基因的分析将揭示针对禽病毒病原体的防御机制。
