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

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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.