Researchers from Imperial College, London and Harvard University, have succeeded in elucidating the structure of integrase, the enzyme which is responsible for copying the DNA of HIV into the cells of people infected by the retrovirus.
Prior to this many researchers have tried to work out the three-dimensional structure of integrase bound to viral DNA. While antiretroviral drugs for HIV work by blocking integrase, it is not understood exactly how these drugs interact with the enzyme, or how to improve them.
In this study, the researchers used a version of integrase borrowed from a little-known retrovirus called Prototype Foamy Virus (PFV), to grow a crystal of the enzyme for analysis. In four years the researchers carried out over 40,000 trials, from which they were able to grow just seven kinds of crystals. Only one of these was of sufficient quality to allow determination of the three-dimensional structure of the enzyme.
After growing the crystals in the lab, the researchers used the synchrotron at the UK’s Diamond Light Source to determine structure. They also observed for the first time how antiretroviral drugs bind to and inactivate integrase.
It turns out that retroviral integrase has quite a different structure from that which had been predicted in earlier research. Working from the structure it will be possible to determine exactly how integrase inhibitors work, how they might be improved, and develop strategies to prevent HIV developing resistance to them.