Enzyme structure cracks HIV puzzle

AIDS researchers have solved a 20-year-old puzzle regarding a key component of HIV, a discovery that could lead to better treatments.

Scientists at Imperial College London and Harvard University revealed the structure of an enzyme called integrase, which HIV uses to copy its genetic information into a person's DNA.

"Despite initially painstakingly slow progress and very many failed attempts, we did not give up and our effort was finally rewarded," said Peter Cherepanov of Imperial College London, the study's lead author, in a statement.

HIV infects a person by copying its DNA into the host DNA, hijacking the cell's mechanisms to make more viruses. Integrase is a protein catalyst, or enzyme, to allow this copying to take place.

Some AIDS drugs work by inhibiting integrase, but without a three-dimensional structure of the enzyme, scientists weren't sure how those drugs actually worked.

Researchers determine the three-dimensional structure of complex proteins, like enzymes, by growing high-quality crystals. In four years of research and over 40,000 trials, the researchers were able to grow seven kinds of crystals.

Of those, only one was good enough in quality to determine its three-dimensional structure.

"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," said Cherepanov.

Help to improve drugs

The scientists used a version of integrase from another retrovirus, called prototype foamy virus (PFV), in their research. The researchers said that PFV's enzyme is very similar to HIV's version.

The researchers analyzed the crystals using X-ray diffraction at the Diamond Light Source synchrotron in South Oxfordshire, U.K.

They then exposed the integrase crystals to anti-retroviral drugs that inhibit the enzyme's function to observe for the first time exactly how these drugs work.

The structure of the enzyme and the mechanism of the anti-retroviral drugs will help scientists improve the drugs and help prevent the virus from developing resistance to them.

There were approximately 33.4 million people living with HIV in 2008 an increase of 400,000 over the previous year. About 2.0 million AIDS-related deaths were recorded in the same year.

In 2008, 2.7 million people were newly infected with HIV. Of the total, 71 per cent of the new infections occurred in Sub-Saharan Africa. The report also noted the spread of HIV seems to have peaked in 1996 when there were about 3.5 million new infections.

The research was published this week in Nature.