Tartour Kevin, Nguyen Xuan-Nhi, Appourchaux Romain, Assil Sonia, Barateau Véronique, Bloyet Louis-Marie, Burlaud Gaillard Julien, Confort Marie-Pierre, Escudero-Perez Beatriz, Gruffat Henri, Hong Saw See, Moroso Marie, Reynard Olivier, Reynard Stéphanie, Decembre Elodie, Ftaich Najate, Rossi Axel, Wu Nannan, Arnaud Frédérick, Baize Sylvain, Dreux Marlène, Gerlier Denis, Paranhos-Baccala Glaucia, Volchkov Viktor, Roingeard Philippe, Cimarelli Andrea
CIRI, Centre International de Recherche en Infectiologie, Lyon, France.
INSERM, U1111, Lyon, France.
PLoS Pathog. 2017 Sep 28;13(9):e1006610. doi: 10.1371/journal.ppat.1006610. eCollection 2017 Sep.
IFITMs are broad antiviral factors that block incoming virions in endosomal vesicles, protecting target cells from infection. In the case of HIV-1, we and others reported the existence of an additional antiviral mechanism through which IFITMs lead to the production of virions of reduced infectivity. However, whether this second mechanism of inhibition is unique to HIV or extends to other viruses is currently unknown. To address this question, we have analyzed the susceptibility of a broad spectrum of viruses to the negative imprinting of the virion particles infectivity by IFITMs. The results we have gathered indicate that this second antiviral property of IFITMs extends well beyond HIV and we were able to identify viruses susceptible to the three IFITMs altogether (HIV-1, SIV, MLV, MPMV, VSV, MeV, EBOV, WNV), as well as viruses that displayed a member-specific susceptibility (EBV, DUGV), or were resistant to all IFITMs (HCV, RVFV, MOPV, AAV). The swapping of genetic elements between resistant and susceptible viruses allowed us to point to specificities in the viral mode of assembly, rather than glycoproteins as dominant factors of susceptibility. However, we also show that, contrarily to X4-, R5-tropic HIV-1 envelopes confer resistance against IFITM3, suggesting that viral receptors add an additional layer of complexity in the IFITMs-HIV interplay. Lastly, we show that the overall antiviral effects ascribed to IFITMs during spreading infections, are the result of a bimodal inhibition in which IFITMs act both by protecting target cells from incoming viruses and in driving the production of virions of reduced infectivity. Overall, our study reports for the first time that the negative imprinting of the virion particles infectivity is a conserved antiviral property of IFITMs and establishes IFITMs as a paradigm of restriction factor capable of interfering with two distinct phases of a virus life cycle.
干扰素诱导跨膜蛋白（IFITMs）是一类广泛的抗病毒因子，可在内体小泡中阻断进入的病毒粒子，保护靶细胞免受感染。就人类免疫缺陷病毒1型（HIV-1）而言，我们和其他研究人员报告称存在另一种抗病毒机制，通过该机制IFITMs可导致产生感染性降低的病毒粒子。然而，这种第二种抑制机制是否为HIV所特有，或者是否也适用于其他病毒，目前尚不清楚。为了解决这个问题，我们分析了多种病毒对IFITMs对病毒粒子感染性的负面印记作用的敏感性。我们收集的结果表明，IFITMs的这种第二种抗病毒特性远远超出了HIV的范围，我们能够鉴定出对所有三种IFITMs均敏感的病毒（HIV-1、猴免疫缺陷病毒（SIV）、莫洛尼鼠白血病病毒（MLV）、猴泡沫病毒（MPMV）、水疱性口炎病毒（VSV）、麻疹病毒（MeV）、埃博拉病毒（EBOV）、西尼罗河病毒（WNV）），以及表现出成员特异性敏感性的病毒（爱泼斯坦-巴尔病毒（EBV）、杜格贝病毒（DUGV）），或对所有IFITMs均耐药的病毒（丙型肝炎病毒（HCV）、裂谷热病毒（RVFV）、莫科拉病毒（MOPV）、腺相关病毒（AAV））。抗性病毒和敏感病毒之间的遗传元件交换使我们能够指出病毒组装模式的特异性，而不是糖蛋白作为敏感性的主要因素。然而，我们还表明，与X嗜性、R嗜性HIV-1包膜赋予对IFITM3的抗性相反，这表明病毒受体在IFITMs与HIV的相互作用中增加了另一层复杂性。最后，我们表明，在病毒传播感染期间归因于IFITMs的总体抗病毒作用是一种双峰抑制的结果，其中IFITMs既通过保护靶细胞免受进入病毒的感染，又通过驱动产生感染性降低的病毒粒子来发挥作用。总体而言，我们的研究首次报告病毒粒子感染性的负面印记是IFITMs的一种保守抗病毒特性，并将IFITMs确立为一种能够干扰病毒生命周期两个不同阶段的限制因子范例。
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