Comparative genome analysis suggests that vertebrates and retroviruses have co-existed for tens of millions of years.
It is thus unsurprising that a degree of co-evolution has taken place, resulting in the development of specific defence mechanisms by the host, and means to overcome such defences by the virus. Understanding such natural anti-viral genes might suggest novel means of combating retroviral infection. Such studies form the basis of a long-standing collaboration with the group of Ian Taylor.
The primate TRIM5α genes provide an example of such a host defence gene. They can interact with the polymerised viral capsid proteins present on infecting retroviruses. One key question in their study concerns the specificity of target recognition. On the one hand, they are capable of recognising and restricting a wide range of viruses. However, each TRIM5α restricts a different panel of viruses.
We are attempting to define the sequences responsible for recognition of different viruses and to describe the structures with which they interact. Similar studies are also underway for a second capsid binding restriction factor, Fv1. We anticipate that these studies will shed new light on the early stages of retrovirus replication and the control of cross-species infection.
Some retroviruses encode accessory proteins that serve as countermeasures to disable host defences. Restriction factors and accessory proteins are engaged in an evolutionary "molecular arms race" consisting of multiple rounds of host adaptation, virus counteraction, and host re-adaptation, resulting in accumulation of amino acid changes in restriction factor-accessory protein interaction interfaces. We are now examining the evolution, targets and modes of action of two such lentiviral accessory proteins, Vpx and Vpr.