HIV researchers solve key puzzle after 20 years of trying
Team has grown crystal that reveals structure of an enzyme called integrase, which is found in retroviruses like HIV
February 1, 2010 - Researchers have made a breakthrough in HIV research that had eluded scientists for over 20 years,
potentially leading to better treatments for HIV, in a study published today in the journal Nature.
The researchers, from Imperial College London and Harvard University, have grown a crystal that reveals the structure of an
enzyme called integrase, which is found in retroviruses like HIV. When HIV infects someone, it uses integrase to paste a copy of its genetic
information into their DNA.
Prior to the new study, which was funded by the Medical Research Council and the US National Institutes of Health,
many researchers had tried and failed to work out the three-dimensional structure of integrase bound to viral DNA. New antiretroviral drugs
for HIV work by blocking integrase, but scientists did not understand exactly how these drugs were working or how to improve them.
Researchers can only determine the structure of this kind of molecular machinery by obtaining high quality crystals.
For the new study, researchers grew a crystal using a version of integrase borrowed from a little-known retrovirus called Prototype Foamy Virus
(PFV). Based on their knowledge of PFV integrase and its function, they were confident that it was very similar to its HIV counterpart.
Over the course of four years, the researchers carried out over 40,000 trials, out of 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.
Dr Peter Cherepanov , the lead author of the study
from the Department of Medicine at Imperial College London, said: "It is a truly amazing story. When we started out, we knew that the
project was very difficult, and that many tricks had already been tried and given up by others long ago. Therefore, we went back to
square one and started by looking for a better model of HIV integrase, which could be more amenable for crystallization. Despite
initially painstakingly slow progress and very many failed attempts, we did not give up and our effort was finally rewarded."
After growing the crystals in the lab, the researchers used the giant synchrotron machine at the Diamond Light Source in South Oxfordshire
to collect X-ray diffraction data from these crystals, which enabled them to determine the long-sought structure. The researchers then soaked
the crystals in solutions of the integrase inhibiting drugs Raltegravir (also known as Isentress) and Elvitegravir and observed for the first
time how these antiretroviral drugs bind to and inactivate integrase.
The new study shows that retroviral integrase has quite a different structure to that which had been predicted based on earlier
research. Availability of the integrase structure means that researchers can begin to fully understand how existing drugs that inhibit
integrase are working, how they might be improved, and how to stop HIV developing resistance to them.
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Notes to editors:
1. "Retroviral intasome assembly and inhibition of DNA strand transfer" Nature , Sunday 31 January 2010
Lead author: Peter Cherepanov, Imperial College London (for full author details please see paper)
2. For almost 100 years the Medical Research Council has improved the health of people in the UK and around the world by supporting the
highest quality science. The MRC invests in world-class scientists. It has produced 29 Nobel Prize winners and sustains a flourishing
environment for internationally recognised research. The MRC focuses on making an impact and provides the financial muscle and
scientific expertise behind medical breakthroughs, including one of the first antibiotics penicillin, the structure of DNA
and the lethal link between smoking and cancer. Today MRC funded scientists tackle research into the major health
challenges of the 21st century. www.mrc.ac.uk
3. About Imperial College London
Consistently rated amongst the world's best universities, Imperial College London is a science-based institution with a reputation for excellence
in teaching and research that attracts 14,000 students and 6,000 staff of the highest international quality.
Innovative research at the College explores the interface between science, medicine, engineering and business, delivering practical solutions that
improve quality of life and the environment - underpinned by a dynamic enterprise culture.
Since its foundation in 1907, Imperial's contributions to society have included the discovery of penicillin, the development of holography and the
foundations of fibre optics. This commitment to the application of research for the benefit of all continues today, with current focuses including
interdisciplinary collaborations to improve health in the UK and globally, tackle climate change and develop clean and sustainable sources of energy.
Source: Imperial College London