Large DNA Virus Assembly

Our group studies how large DNA viruses build their virions. Our research aims at understanding how viral structures emerge, change during virus morphogenesis and finally produce an infectious virion. In addition, we are particularly interested in understanding how membranes from the infected cells are co-opted to promote replication and virion assembly. We study these processes primarily in poxviruses, including orthopoxviruses and capripoxviruses. These viruses remain a threat to human and animal health and provide an exceptional model to study the assembly of complex enveloped viruses in the cytoplasm of infected cells.

Poxviruses stand among the most complex viruses causing disease in animals and humans. After smallpox eradication, vaccination efforts stopped, leaving human populations susceptible to poxvirus infections. Moreover, with antivirals being scarce and animal reservoirs abundant, the spread of monkeypox worldwide further underscores the need to control animal poxviruses and be prepared against future epidemics. Poxviruses replicate in the cytoplasm of infected cells, where the viral genome, viral proteins and membranes from the infected cell come together to form a functional, infectious particle.

During infection, poxviruses co-opt cellular membranes to assemble non-infectious immature virions. Virion maturation then involves a dramatic structural reorganisation, where a multilayered core containing the genome forms. How such dramatic structural transformation occurs to produce an infectious virion is largely unknown. We are using biochemistry, virology, cell biology and imaging methods to understand poxvirus assembly and how virion structure promotes infection. By uncovering fundamental mechanisms used to assemble complex virions inside cells, our research will identify novel targets for antivirals. Insights gained from poxviruses, will be extended to their closest relative, African Swine Fever Virus (ASFV), which causes a devastating haemorrhagic disease in pigs. ASFV seems to assemble infectious virions in a remarkable similar fashion to poxviruses but differs in the way virions leave the cell. This salient difference between the two otherwise similar morphogenetic pathways offers a unique opportunity to uncover fundamental mechanisms by which large DNA viruses assemble while co-opting host membranes.

In summary, we aim to reveal fundamental assembly mechanisms used by large DNA viruses, which will help identify antiviral targets and inform vaccine development. In addition, our research sheds light on host-pathogen interactions and the organisation of complex biological assemblies involving nucleic acids, proteins and membranes – an essential aspect of life.

Poxviruses have had a major influence on human and animal health throughout history and continue to pose a risk to both. Capripoxviruses, which can be devastating for cattle, sheep and goats, have recently spread out of their endemic areas into Europe and Asia, while the emergence of monkeypox has highlighted the zoonotic threat to human health of poxviruses. Furthermore, ASFV lacks available vaccines or antivirals and is spreading across Europe.

By understanding the assembly of large DNA viruses, we are defining molecular processes that can be targeted by future antivirals and informing the rational design of safer and more effective vaccines.

Our work provides a fundamental framework for understanding virus morphogenesis, evolution and infection, contributing to Pirbright’s mission to protect animal and human health through research in viral diseases.