We are interested in how retroviruses interact with the host and how these interactions dictate species-specific replication. For example, HIV-1 replicates in humans, chimpanzees and possibly gorillas but not in other primates like African monkeys. The reason for species specificity is not entirely clear but depends to some degree on species-specific antiviral factors called restriction factors. Restriction factors are part of the innate immune system and specifically target viruses and protect the host. A better understanding of restriction factors promises to improve animal models for infection, identify targets for antiviral therapies, and further facilitate the use of viral vectors for clinical and investigative gene delivery. We work on two restriction factors. The tripartite motif protein TRIM5 blocks infection by coating incoming viruses and then recruiting them to the proteasome for destruction. Antiviral specificity is determined by the sequence of the C-terminal viral binding B30.2 domain. Remarkably, on 2 separate occasions during primate evolution the B30.2 domain has been replaced by a protein called cyclophilin A (CypA) to make so called TRIMCyp proteins. It appears that, like the B30.2 domain, CypA is an excellent lentiviral binding protein and its plasticity allows point mutants to switch binding specificity between different lineages of primate lentiviruses. We also work on a restriction factors called tetherin, which tethers newly formed virions to infected cells preventing their release. Viruses are obliged to antagonise tetherin and HIV-1 does this using its Vpu protein, which causes tetherin destruction. Some SIVs without a Vpu protein sequester tetherin using their envelope proteins. We are considering the mechanisms of TRIM5 and tetherin and whether they restrict other viruses such as herpes viruses. We would also like to know how lentiviruses like HIV-1 manage to avoid activating pattern recognition pathways despite infecting immune cells and how viral uncoating and nuclear entry relate to this these processes.
Our work is influenced by Leigh Van Valen's Red Queen hypothesis. In Lewis Carroll's "Through the Looking Glass" the Red Queen said to Alice "It takes all the running you can do to stay in the same place". This is likened to the arms race that exists between pathogens and their hosts. Continuous evolutionary change (running) is required on both sides to maintain the status quo. We have shown that analysis of positive selection and sequence change in hosts (tetherin and TRIMCyp) and in viral capsids reveals how change influences restriction and replication. Remarkably, point mutations in either virus or host can switch between restriction and successful replication indicating that the balance between immunity and disease is often delicate. Our work is funded by The Wellcome Trust the Medical Research Council and the National Institute of Health Research UCL/UCLH Comprehensive Biomedical Research Centre.