Distinct functional determinants of influenza hemagglutinin-mediated membrane fusion.
Distinct functional determinants of influenza hemagglutinin-mediated membrane fusion.
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DOI：
10.7554/elife.11009
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发表时间：
2015-11-27
期刊：
影响因子：
7.7
通讯作者：
Harrison SC
中科院分区：
文献类型：
--
作者：
Ivanovic T;Harrison SC
膜融合是包膜病毒穿透感染细胞的关键步骤。我们以前曾使用单病毒粒子融合动力学的测量研究流感病毒包膜融合的分子机制。关于流感病毒血凝素（HA）“干”抗体融合抑制的已发表数据现在允许我们将一些HA无活性的规定纳入模拟中。我们发现，超过一半的HA是非生产性的，即使没有结合抗体的病毒粒子，但整体机制是非常强大的。确定主管HA的分数允许我们确定它们的靶膜接合速率。模拟与H3N2和H1N1病毒的数据比较揭示了HA介导的膜融合与中和敏感性密切相关的三个独立的功能变量。在进化机制中的补偿性变化的证据为旨在定义HA进化性的分子限制的研究奠定了基础。DOI：www.example.com流感（或流感）病毒可以感染人类和其他动物，并可能导致危及生命的疾病。为了繁殖，病毒颗粒必须首先进入宿主细胞。进入过程的最后一步是流感病毒周围的膜与宿主细胞的膜融合。这一事件将病毒颗粒的核心释放到细胞中，在那里它可以刺激细胞产生更多的病毒拷贝。为了确保膜融合在正确的时间和地点发生，流感病毒用一种称为血凝素的蛋白质装饰其膜表面。这种蛋白质感知靶细胞提供的信号，然后经历一系列转化，导致膜融合。在此过程中，血凝素分子插入靶细胞膜，将病毒和细胞膜结合在一起。2013年，一组研究人员开发了一种计算机模拟算法来研究导致膜融合的事件。在该模型中，病毒颗粒上的血凝素分子被随机激活，插入细胞膜。现在，Ivanovic和Harrison-早期工作的两名研究人员-将该模型的预测与先前流感病毒颗粒膜融合研究的实验数据进行了比较。这种方法表明，相当一部分血凝素分子无法接触靶细胞膜，而是永久失活。尽管如此，核聚变仍能有效地进行。Ivanovic和Harrison认为，这些不活跃的血凝素提供了一个进化的后备库。例如，插入细胞膜的病毒颗粒上的血凝素的比例影响融合发生的速度以及病毒对称为抗体的宿主免疫系统蛋白质攻击的敏感程度。因此，控制血凝素插入细胞膜的频率的能力可以使病毒适应宿主的免疫反应。将来，伊万诺维奇和哈里森的发现可能有助于发现抑制流感进入人体细胞的药物。DOI：www.example.com网站
Membrane fusion is the critical step for infectious cell penetration by enveloped viruses. We have previously used single-virion measurements of fusion kinetics to study the molecular mechanism of influenza-virus envelope fusion. Published data on fusion inhibition by antibodies to the 'stem' of influenza virus hemagglutinin (HA) now allow us to incorporate into simulations the provision that some HAs are inactive. We find that more than half of the HAs are unproductive even for virions with no bound antibodies, but that the overall mechanism is extremely robust. Determining the fraction of competent HAs allows us to determine their rates of target-membrane engagement. Comparison of simulations with data from H3N2 and H1N1 viruses reveals three independent functional variables of HA-mediated membrane fusion closely linked to neutralization susceptibility. Evidence for compensatory changes in the evolved mechanism sets the stage for studies aiming to define the molecular constraints on HA evolvability. DOI: http://dx.doi.org/10.7554/eLife.11009.001 Influenza (or flu) viruses can infect humans and other animals and can lead to life-threatening illness. To multiply, the virus particles must first enter a host cell. The final step in the entry process is the fusion of the membrane that surrounds the influenza virus with the membrane of the host cell. This event releases the core of the virus particle into the cell, where it can stimulate the cell to make more copies of the virus. To ensure that membrane fusion takes place at the right place and time, influenza virus decorates the surface of its membrane with a protein called hemagglutinin. This protein senses cues provided by the target cell and then undergoes a series of transformations that lead to membrane fusion. During this process, hemagglutinin molecules insert into the target cell membrane to bring together the viral and cellular membranes. In 2013, a group of researchers developed a computer simulation algorithm to study the events that lead to membrane fusion. In the model, the hemagglutinin molecules on a virus particle are activated at random to insert into the cell membrane. Now, Ivanovic and Harrison – two of the researchers from the earlier work – compared the predictions of this model to experimental data from previous studies of membrane fusion by influenza virus particles. This approach shows that a substantial fraction of hemagglutinin molecules fail to contact the target-cell membrane and are permanently inactivated instead. Fusion nonetheless proceeds efficiently. Ivanovic and Harrison suggest that these inactive hemagglutinins provide an evolutionary backup store. For example, the proportion of hemagglutinins on a virus particle that insert into the cell membrane affects how fast fusion occurs and how sensitive the virus is to attack by host immune-system proteins called antibodies. Therefore, an ability to control how often hemagglutinins insert into the membrane could allow the virus to adapt to host immune responses. In the future, Ivanovic and Harrison’s findings could aid the discovery of drugs that inhibit the entry of influenza into human cells. DOI: http://dx.doi.org/10.7554/eLife.11009.002