Exploring the world of giant viruses using structural biology

The discovery of giant viruses, comparable in size and complexity to simple cellular organisms has pushed back the frontier of the virus world. Poxviruses are the largest human viral pathogens and model systems for this group of diverse viruses, which have a unique place in virus evolution. In these viruses, membrane acquisition is critical to virulence but poorly understood. This process departs from known membrane remodeling strategies used by cellular organisms and classical enveloped viruses. The proposed research focuses on elucidating the structure-function of the multi-protein complex that is responsible for the assembly of internal membranes in the infectious particles of these viruses. The project combines structural biology approaches including X-ray crystallography and cryo electron microscopy (cryoEM) to build a molecular model of virus-induced membrane assembly. In vaccinia virus and smallpox, the membrane assembly machinery is the target of the antibiotic rifampicin, which represents a rare example of a molecule exhibiting dual antibacterial and antiviral activities with very different targets. Thus, this project will also contribute to the development of improved antiviral molecules targeting this step by interfering with the interactions between key proteins and their lipidic ligands.