Human rhinovirus VP4: membrane pore-forming capsid protein and conserved target for broadly neutralising antibodies

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。HRV感染还与更严重的临床后果有关，如婴儿严重下呼吸道感染和哮喘等慢性肺部疾病的恶化。病毒必须进入宿主细胞才能开始感染，而细胞膜是病毒必须穿透的屏障。对于许多病毒来说，实现这一目标的过程并不是很清楚。HRV是一种非常简单的病毒，这为更详细地理解这一过程提供了一个很好的模型系统。该病毒由包裹在蛋白质壳或衣壳中的单链RNA(病毒基因组，制造新病毒的蓝图)组成。根据以前的实验，我们认为在进入细胞的过程中，病毒会释放一种名为VP4的内部衣壳蛋白，在膜上形成一个孔，通过这个孔将RNA输送到细胞内。宿主对病毒感染的免疫反应通常会产生抗体，与病毒结合，从而控制感染。通常情况下，一种病毒可以作为几种毒株或类型在其外表面发生变异而传播，因此抗体只能识别一种特定的病毒类型并提供保护。就HRV而言，有100多种不同的类型，这被认为可以解释为什么感冒如此频繁，并限制了疫苗的前景。与大多数衣壳不同，VP4蛋白在HRV类型之间高度保守，以前的实验表明，抗VP4的抗体可以中和多种类型的HRV。我们将进行研究，以获得新的理解，以获得VP4如何在膜上形成孔，它如何从颗粒中出现，以及抗VP4的抗体如何对多种类型的病毒具有广泛的中和活性。

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. HRV infection is also associated with more serious clinical outcomes such as severe lower respiratory tract infections of infants and exacerbations of chronic lung diseases such as asthma. Viruses must gain entry to host cells for infection to begin and the membrane of the cell presents a barrier which the virus must penetrate. For many viruses, the process by which this is achieved is not well understood. HRV is a very simple virus which makes a good model system for understanding this process in more detail. The virus comprises a single strand of RNA (the virus genome, the blueprint for making new virus) enclosed in a protein shell or capsid. Based on previous experiments we believe that during entry to the cell, a small internal capsid protein called VP4 is released from the virus to form a pore in the membrane through which the RNA is delivered into the cell.The host immune response to a virus infection often produces antibodies which bind to the virus and bring the infection under control. Often a virus can circulate as several strains or types with variation in their outer surface such that antibodies will only recognise and provide protection against one specific virus type. In the case of HRV there are over 100 different types which is thought to explain why colds are so frequent and has limited the prospects of a vaccine. Unlike most of the capsid, the VP4 protein is highly conserved between HRV types and previous experiments showed that antibodies against VP4 can neutralise multiple types of HRV. We will carry out studies to gain novel understanding of how VP4 forms the pore in the membrane, how it emerges from the particle and how antibodies against VP4 can have broadly neutralising activity against multiple types of the virus.