Picornavirus capsid protein VP4: Essential role in cell entry and conserved antiviral target

小核糖核酸病毒家族包括人鼻病毒、脊髓灰质炎病毒和肠道病毒71等病毒。人类鼻病毒(HRV)感染人类的频率比任何其他病毒都高，约占所有亚临床呼吸道感染(普通感冒)的70%，每年造成英国数十亿英镑的损失。尽管进行了数十年的研究，但仍然没有获得许可的预防或减少感染的药物。脊髓灰质炎病毒(PV)是正在进行的全球根除运动的主题，但随着我们接近根除的最后阶段，一些专家认为，迫切需要为根除后时代制定新的额外控制战略。直到最近，人们还认为肠道病毒71型只会引起幼儿的一种一般轻微的疾病(手足口病)。然而，近年来，EV71型肠病毒大规模爆发，席卷了中国和东南亚，病例达到10万例，包括更严重的疾病和数以百计的儿童死亡。目前还没有疫苗或抗病毒药物。短小核糖核酸病毒通过劫持细胞机器来感染细胞，以便通过内化的膜泡进入细胞。为了开始感染，病毒基因组(制造新病毒的蓝图)必须通过这个囊泡的膜传递到细胞质，细胞质是病毒复制发生的细胞间。该病毒用于基因组传递的机制尚不清楚。更详细地了解这一过程将为开发干扰细胞进入的抗病毒药物提供有价值的见解。病毒基因组包含在蛋白质外壳或衣壳内。衣壳保护基因组免受环境破坏，也是一种动态结构，在细胞进入过程中起着至关重要的作用。实验表明，在进入细胞的过程中，其中一种衣壳蛋白VP4会从病毒中出来，并与膜相互作用。对突变病毒的实验已经证实，VP4参与了进入过程。我们使用了模型膜和重组VP4，这为研究蛋白质-膜相互作用和膜通透性提供了一个方便的系统。我们已经证明VP4能够与脂质体相互作用，并通过形成多聚体孔来诱导膜通透性。因此，我们认为VP4在细胞进入过程中起着膜孔的作用：在膜上的‘孔’，通过它病毒基因组被输送到细胞质。我们认为，我们应该更详细地研究VP4的作用，以便开发与VP4相互作用的分子或药物，阻断其功能，防止感染。

The picornavirus family includes viruses such as human rhinovirus, poliovirus and enterovirus 71. Human rhinovirus (HRV) infects humans more frequently than any other virus and is responsible for approximately 70% of all subclinical respiratory infections (the common cold) which costs the UK £billions every year. Despite decades of research there remains no licensed drug to prevent or reduce infection. Poliovirus (PV) is the subject of an ongoing world-wide eradication campaign but as we reach closer to the final stages of eradication, some experts believe there is an urgent need for additional novel control strategies for the post-eradication era. Enterovirus 71 was until recently only thought to cause a generally mild disease of young children (hand-foot-and-mouth disease). However, in recent years huge outbreaks of EV71 have swept across China and Southeast Asia with cases in the 100,000s including more severe disease and hundreds of child deaths. No vaccine or antiviral is available.Picornaviruses infect cells by hijacking cellular machinery in order to be taken into the cell within an internalised membrane vesicle. For infection to begin, the virus genome (the blueprint for making new virus) must be delivered through the membrane of this vesicle, to reach the cytoplasm, the compartment of the cell where virus replication occurs. The mechanism used by the virus for genome delivery remains unclear. Understanding this process in more detail will provide valuable insights for the development of antiviral agents that interfere with cell entry.The viral genome is contained within a protein coat or capsid. The capsid protects the genome from environmental damage and is also a dynamic structure which plays a crucial role in the cell entry process. Experiments have shown that during cell entry, one of the capsid proteins, VP4, comes out of the virus and interacts with the membrane. Experiments with mutated viruses have confirmed that VP4 is involved in the entry process. We have used model membranes and recombinant VP4 which provide a convenient system for investigating protein-membrane interactions and membrane permeability. We have demonstrated that VP4 is able to interact with liposomes and induce membrane permeability by forming a multimeric pore. We therefore propose that VP4 functions as a membrane pore during cell entry: the 'hole' in the membrane through which the virus genome is delivered into the cytoplasm. We believe that we should study the role of VP4 in more detail in order to develop molecules or drugs that interact with VP4, block its function and prevent infection.