Structural studies of human viruses and host interactions

Virus particles are dynamic structures that replicate inside the cells of their host. We wish to understand their structure and how they interact with the cell. This can provide insights into many aspects of virus biology and may suggest strategies for treatment. The viruses being studied include measles virus, viruses that cause respiratory illnesses (influenza virus and respiratory syncytial virus), viruses that cause liver disease (Hepatitis B and C viruses) and viruses related to those that cause winter vomiting disease (Caliciviruses and Norovirus). We are determining the three-dimensional structures of the viruses at different stages during their replication and as they interact with host molecules to determine how their form relates to their function. We are also interested in the use of viruses to prevent disease through development of novel vaccines.

Knowledge of the structure of viruses and how they interact with the host cell is essential for understanding the processes involved in infection. Virion morphogenesis is a central feature of the life cycle of any virus, and a clear understanding of this process can provide insights into many aspects of virus biology and may suggest possible strategies for therapeutic intervention. We use both cryogenic electron microscopy and tomography to visualise virus particles at various stages during their replication. Five virus families that cause disease in humans are currently under study; caliciviruses and hepaciviruses (positive strand RNA viruses), orthomyxoviruses and paramyxoviruses (negative strand RNA viruses) and hepadnaviruses (double-stranded DNA viruses).
Paramyxoviruses (measles and respiratory syncytial virus) have characteristic, helical ribonucleoprotein (RNP) cores that act as the templates for genome replication and expression. We are interested in investigating these structures as they undergo their different biological processes: mRNA and genomic RNA synthesis and packaging during virion morphogenesis. Virus assembly in Orthomyxoviruses (Influenza viruses) and Paramyxoviruses leads to both filamentous and spherical forms of enveloped virions. Cryotomography approaches are being used to analyse asymmetric entities such as these, as well as virus-infected cells. In particular we are interested in applying 3D imaging to the study of more biologically relevant cell systems that mimic the host tissue in which infection takes place.
Caliciviruses, hepaciviruses and hepadnaviruses all have icosahedral particles, which in hepaci and hepadnaviruses are surrounded by a lipid envelope. Icosahedral reconstruction is being used to investigate the structure of hepadnavirus capsids that have been modified to display foreign epitopes for use both as a vaccine candidate and also to solve the structure of the inserted polypeptides. We are studying virus entry and tropism in calicivirus and hepaciviruses by investigating the interaction between particles and specific host molecules: cellular receptors, neutralising antibodies. Knowledge of these interactions can inform vaccine design and development of antiviral therapies.