Cell Reports：IFITM跨膜蛋白阻止和抑制细胞间的HIV传输

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毫无疑问，人类免疫缺陷病毒也就是艾滋病毒是毁灭性的。在美国超过120万人感染艾滋病毒，每年有超过47000人被诊断出有艾滋病。现在，密苏里大学的研究人员发现了一种专门的蛋白可以抑制病毒发展。

人类细胞表达干扰素诱导的跨膜(IFITM)蛋白质具有抗病毒特性。这些蛋白可以抑制多种病毒包括甲型流感、西尼罗病毒、登革热和埃博拉病毒。在他的研究中，Shan-Lu Liu是分子微生物学和免疫学副教授，也是在密苏里大学医学院生命科学中心的一名调查员，研究目标是IFITM蛋白质及其抗病毒功能。

“我们早就知道IFITM蛋白质有抗病毒作用，但直到现在我们没有确切了解蛋白质特别是如何抑制艾滋病毒的传播的。”刘说。“我们知道HIV - 1是最常见的HIV病毒株，可以在细胞间传播或通过无细胞传播。我们的研究发现，IFITM蛋白质可以在细胞间帮助抑制滤过性毒菌引起的病毒感染，这是艾滋病传播最有效的方法。”

Jingyou Yu博士是密苏里大学病理学研究生，他进行的实验表明IFITM蛋白质，尤其是IFITM2和IFITM3，可以阻止艾滋病毒细胞间传播。Minghua Li也是病理学研究生，发现IFITM蛋白质特别是与hiv - 1包膜糖蛋白相互作用并抑制其成熟病毒传染性和传输的需要。此外，liu曾在加拿大和纽约研究实验室重现和验证他的发现。

“这一发现十分意外，之前在《PLoS Pathogens 》的发现，我们发现，这个种类的蛋白质通常影响细胞膜的脂质属性和阻碍不同的病毒与宿主细胞的融合。”刘说。“在艾滋病毒和艾滋病的研究中，科学家们不断学习更多关于病毒传播和病毒感染宿主反应。通过理解IFITM蛋白如何抑制和阻止传播，我们就会越来越接近找到更好的治疗方法来对抗艾滋病毒。”

来源：生物谷

rentianyixu

正常人体细胞能够表达一类叫做干扰素诱导性跨膜蛋白（Interferon Induced Transmembranes, IFITMs）。刘善虑教授的实验室对IFITM 蛋白以及其抗病毒机制进行了详细的研究，发现IFITM蛋白能够特异地与HIV-1囊膜糖蛋白相互作用，进而抑制后者的加工成熟，而囊膜的成熟对HIV-1的感染性以及传播能力至关重要。

刘善虑教授本科毕业于河南医科大学（现郑州大学医学院），后考入中国预防医学科学院（现CDC）病毒学研究所攻读硕士研究生。他于2003年获华盛顿大学（University of Washington）病理系（Department of Pathology）博士学位，2005 -2010年任麦吉尔大学（McGill University）微生物与免疫学系助理教授，2010年至今为美国密苏里大学（University of Missouri）医学院分子微生物学与免疫学系终身教授。主要从事病毒侵入细胞机制、病毒免疫逃逸机制、病毒复制机制以及抗病毒分子的筛选等方面的研究工作。在Science、PLOS PATHOGENS、PNAS、Oncogene、Cell Reports, Journal of Virology、JBC等期刊发表多篇论文，目前担任Journal of Virology、Virology、Viruses、Cancer Research 、PLoS Pathogens 等杂志的编辑和审稿人。

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另外再附上该实验室发表在《PLoS Pathogens 》的工作

IFITM Proteins Restrict Viral Membrane Hemifusion

Kun Li , Ruben M. Markosyan , Yi-Min Zheng , Ottavia Golfetto, Brittani Bungart, Minghua Li, Shilei Ding, Yuxian He, Chen Liang, James C. Lee, Enrico Gratton, Fredric S. Cohen, Shan-Lu Liu

Abstract

The interferon-inducible transmembrane (IFITM) protein family represents a new class of cellular restriction factors that block early stages of viral replication; the underlying mechanism is currently not known. Here we provide evidence that IFITM proteins restrict membrane fusion induced by representatives of all three classes of viral membrane fusion proteins. IFITM1 profoundly suppressed syncytia formation and cell-cell fusion induced by almost all viral fusion proteins examined; IFITM2 and IFITM3 also strongly inhibited their fusion, with efficiency somewhat dependent on cell types. Furthermore, treatment of cells with IFN also markedly inhibited viral membrane fusion and entry. By using the Jaagsiekte sheep retrovirus envelope and influenza A virus hemagglutinin as models for study, we showed that IFITM-mediated restriction on membrane fusion is not at the steps of receptor- and/or low pH-mediated triggering; instead, the creation of hemifusion was essentially blocked by IFITMs. Chlorpromazine (CPZ), a chemical known to promote the transition from hemifusion to full fusion, was unable to rescue the IFITM-mediated restriction on fusion. In contrast, oleic acid (OA), a lipid analog that generates negative spontaneous curvature and thereby promotes hemifusion, virtually overcame the restriction. To explore the possible effect of IFITM proteins on membrane molecular order and fluidity, we performed fluorescence labeling with Laurdan, in conjunction with two-photon laser scanning and fluorescence-lifetime imaging microscopy (FLIM). We observed that the generalized polarizations (GPs) and fluorescence lifetimes of cell membranes expressing IFITM proteins were greatly enhanced, indicating higher molecularly ordered and less fluidized membranes. Collectively, our data demonstrated that IFITM proteins suppress viral membrane fusion before the creation of hemifusion, and suggested that they may do so by reducing membrane fluidity and conferring a positive spontaneous curvature in the outer leaflets of cell membranes. Our study provides novel insight into the understanding of how IFITM protein family restricts viral membrane fusion and infection.


Author Summary

Many pathogenic viruses contain an envelope that must fuse with the cell membrane in order to gain entry and initiate infection. This process is mediated by one or more glycoproteins present on the surface of the virions, known as viral fusion proteins. Recently, a family of interferon-inducible transmembrane (IFITM) protein has been shown to block viral infection, including those of highly pathogenic viruses. Here we provide evidence that these IFITM proteins potently suppress membrane fusion induced by representatives of all three classes of viral fusion proteins. Interestingly, we found that the block is not at the steps of receptor binding or low pH that triggers conformational changes of viral fusion proteins required for membrane fusion. Rather, we discovered that the creation of hemifusion, an intermediate in which the outer membranes of the two lipid bilayers have merged but the inner membranes still remain intact is blocked by IFITM proteins. We further demonstrated that overexpression of IFITM proteins rigidify the cell membrane, thereby reducing membrane fluidity and fusion potential. Our study provides novel insight into the understanding of how IFITM proteins restrict viral entry and infection.

http://journals.plos.org/plospat ... ournal.ppat.1003124

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IFITM Proteins Restrict HIV-1 Infection by Antagonizing the Envelope Glycoprotein

Jingyou Yu6, Minghua Li6, Jordan Wilkins, Shilei Ding, Talia H. Swartz, Anthony M. Esposito, Yi-Min Zheng, Eric O. Freed, Chen Liang, Benjamin K. Chen, Shan-Lu Liu

Highlights
•IFITMs inhibit HIV-1 cell-to-cell infection and impair viral infectivity
•IFITMs specifically interact with HIV-1 Env and inhibit Env processing
•IFITM incorporation into HIV-1 virions does not correlate with inhibition
•IFITM inhibition of primate lentiviruses is virus-strain specific

Summary
The interferon-induced transmembrane (IFITM) proteins have been recently shown to restrict HIV-1 and other viruses. Here, we provide evidence that IFITM proteins, particularly IFITM2 and IFITM3, specifically antagonize the HIV-1 envelope glycoprotein (Env), thereby inhibiting viral infection. IFITM proteins interact with HIV-1 Env in viral producer cells, leading to impaired Env processing and virion incorporation. Notably, the level of IFITM incorporation into HIV-1 virions does not strictly correlate with the extent of inhibition. Prolonged passage of HIV-1 in IFITM-expressing T lymphocytes leads to emergence of Env mutants that overcome IFITM restriction. The ability of IFITMs to inhibit cell-to-cell infection can be extended to HIV-1 primary isolates, HIV-2 and SIVs; however, the extent of inhibition appears to be virus-strain dependent. Overall, our study uncovers a mechanism by which IFITM proteins specifically antagonize HIV-1 Env to restrict HIV-1 infection and provides insight into the specialized role of IFITMs in HIV infection.

http://www.cell.com/cell-reports/abstract/S2211-1247(15)00952-3