Dr Colin Crump
Research description
Electron micrograph of a herpes simplex virus type-1 (HSV-1) particle.
Herpesviruses 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. Herpesviruses are very diverse: three groups alpha-, beta- and gammaherpesviruses diverged ~400 million years ago and this is reflected in their genetic and biological diversity. Nevertheless key elements of virus replication, such as the assembly and release of mature virions, appear to be conserved in all these viruses. The assembly of herpesviruses is known to involve the budding of nucleocapsids, together with many tegument proteins, at membranes derived from the trans-Golgi network (TGN) or endosomes. Once formed, the membrane-bound compartments containing the mature virions undergo exocytosis to release infectious viruses from the cell. We are investigating the assembly of the paradigm herpesvirus, Herpes Simplex Virus type 1 (HSV-1) in the several areas of research.
Immunofluorescence image of a cell infected with herpes simplex virus type-1 (HSV-1). The localisation of two different major viral structural proteins is shown in green and red.
- How are herpesvirus envelope proteins localised to the correct membranes for final envelopment? There are at least 15 different viral membrane proteins found in the HSV-1 envelope and their localisation to assembly compartments is crucial for incorporation into the mature virus particle. We are investigating several cellular and viral mediators that control the trafficking of herpesvirus membrane proteins in infected cells.
- What drives the membrane scission that separates the virus from cellular membranes? The cellular Endosome Sorting Complexes Required for Transport (ESCRTs) are a series of multi-protein complexes involved in membrane scission events and are recruited by many enveloped viruses to aid their assembly. Our lab was the first to demonstrate a requirement for ESCRT proteins in HSV-1 assembly. However, the mechanism by which HSV-1 recruits ESCRTs appears to be fundamentally different to other ESCRT-dependent viruses such as human immunodeficiency virus. We have identified a complex series of interactions between HSV-1 tegument and human ESCRT proteins and are investigating the key stages in this process.
- Which interactions between tegument proteins are important for HSV-1 assembly? The tegument is a highly complex structure being composed of up to 24 different viral proteins in HSV-1. We are undertaking research into the interactions between tegument proteins that mediate their incorporation into assembling virions and aid the association of nucleocapsids with viral envelope proteins.
- How are newly synthesised HSV-1 particles released? Very little is known about the mechanisms involved in the exocytosis and release of mature virions from an infected cell. We are currently using a variety of methods to identify viral and cellular proteins that play a role in this process.