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

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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.