The role of endosomal sorting proteins in HSV-1 assembly

The herpesviruses are an important group of pathogens that infect humans and cause several medical problems including cold sores, shingles and glandular fever. Herpesviruses can also increase the risk of certain types of cancer, and can cause life-threatening conditions in immune-suppressed people, such as transplant patients. To be able to treat and control infections by these viruses, it is crucial that we understanding how these viruses infect us, how they produce new copies of themselves, and how they spread to new people. The research being proposed will use cell culture models to study the way in which herpesviruses control our cells own machinery in order to form new copies of the virus. Overall, the information gained from this research will give a greater understanding of how this important family of viruses can infect and replicate in our cells. Such information will hopefully identify new targets that could be inhibited by drugs to combat these viruses and the many diseases caused by them.

Herpesviruses are large, complex DNA viruses that are ubiquitous pathogens of vertebrates. Infections by the eight known human herpesviruses are associated with many serious diseases, including certain lymphomas and life-threatening conditions in immune-suppressed patients. Crucial to our ability to treat and control herpesvirus infection and spread is the understanding of the biology behind viral assembly and egress.

Herpesviruses acquire their final envelope, containing several viral glycoproteins, by the budding of cytoplasmic nucleocapsids across membranes derived from either the trans-Golgi network or endosomes. We now have convincing preliminary evidence that the multivesicular endosome (MVE) sorting machinery is required for this cytoplasmic envelopment of HSV-1, although how this machinery is utilised and regulated by this virus is unknown. This research will be an in depth analysis of the role of the cellular MVE machinery in HSV-1 assembly. Key goals will be demonstrating which components of the multi-protein MVE sorting complexes are necessary and sufficient for HSV-1 envelopment; investigation of the recruitment of MVE machinery to HSV-1 assembly sites; analyses of potentially novel interactions between MVE and viral proteins; and the role of ubiquitin in HSV-1 assembly.