Membrane Traffic Pathways in Viral Replication and Pathogenesis

Whether direct infections of man or infections that impact on domestic animals, crops or the environment in general, virus infections are a major health and economic burdens for mankind. Viruses require cells for infection and replication. Understanding the various ways in which viruses gain entry to cells, exploit cellular mechanisms for their replication and exert their pathogenic potential is key to intervening in these processes. Our work aims to understand aspects of the cell biology of human immunodeficiency viruses (HIV), the infectious agents associated with AIDS, and the arboviruses Dengue virus and Semliki Forest virus, representatives of two families of viruses transmitted by mosquitoes and currently responsible for wide-spread epidemics in the tropics. We will focus on understanding how a set of cellular proteins can prevent specific events in the entry of these viruses into cells, with a view to exploiting these proteins as natural inhibitors of infection. In parallel, we aim to use knowledge acquired over many years to identify broad-spectrum, small molecule, inhibitors of arbovirus infection that can be used as prophylactics or in epidemic situations. We will continue current work on virus assembly, using new methods to understand the cell biology of virus formation and, for HIV in particular, how modification of key signals in viral proteins, required for correct virus assembly, impact on viral pathogenesis.

The mechanisms used by viruses to invade and replicate in cells are of fundamental interest, both in terms of improved understanding of infection and pathogenesis, with implications for health and economic wellbeing, but also because viruses are extraordinary tools for revealing how cells work. Because they have membranes, we are focussed on understanding how enveloped viruses interact with cellular membrane systems, how these interactions facilitate or restrict the transmission of viruses from cell to cell and how they impact on pathogenesis. We are developing these themes through existing and new programs of work with the aim of exploiting our current know-how to develop knowledge-based interventions against viral infection and/or pathogenesis. In new programs of work, we are investigating (1) how interferon-induced transmembrane (IFITM) proteins inhibit the entry of a broad range of enveloped viruses, (2) the potential to develop broad-spectrum antivirals that inhibit the entry of viruses that exploit the same endocytic entry mechanisms, and (3) the cell biological processes underlying virus particle formation.
The work focuses on three new projects developed during the previous QQ. The program synergises with the programs of other MRC LMCB groups, in particular those of Mercer, who is also interested in the cell biology of viral replication, Henriques, with whom we are developing new methods for investigating virus-cell interactions using advanced imaging methods, and Paluch, Cutler, Pichaud, Stefan and Baum, with whom we will collaborate to develop understanding of the mechanisms through which viruses that assemble at the cell surface deform the membrane and overcome the barrier imposed by the cortical cytoskeleton.
Our main objectives are:
1.To determine the molecular mechanism(s) through which IFITM proteins inhibit enveloped virus entry.
2.To use and expand our understanding of arboviruses to develop novel broad-spectrum antivirals.
3.To use novel imaging techniques to further develop our understanding of how HIV and related viruses assemble at the plasma membrane, and to gain insight into how the physical properties of the plasma membrane and cortical cytoskeleton impact on these events.