A team of Harvard researchers have discovered a way to watch how the AIDS virus becomes resistant to drugs. They hope the images will help drug companies devise more effective ways to attack the virus.
Stephen Harrison and his colleagues at Harvard University's Howard Hughes Medical Institute were able to crystallise and make an image of the reverse transcriptase enzyme, which HIV uses to replicate itself. They caught the virus just after it attacked a cell using an instrument known as a synchrotron -- a high-intensity, high-energy X-ray crystallography machine -- to capture the image.
Five HIV drugs now on the market, including the original drug, AZT, target reverse transcriptase. The medications work by mimicking nucleotides, natural building blocks of DNA in the cell. The HIV virus uses nucleotides when it attacks a cell, injecting its own genetic material into them and forcing the cell to produce copies of the virus instead of dividing naturally.
Combined with drugs known as protease inhibitors that attack the virus at a different stage of its life cycle, the approach works fairly well to suppress the viral infection.
In many people, however, HIV eventually mutates and becomes resistant to drugs.
Drug researchers have found that seeing the physical structure of drugs and their biological targets can help them design compounds that work together. Many of them fit together like a lock and key.
The Harvard team confirmed that the virus mutates in specific ways that allow it to effectively ignore the drugs.
"The clustering of the mutations correlates with the chemical structure of the drug," they wrote in a report in the journal Science, published Thursday. X-ray crystallography helped them to see the physical structures.
Other scientists have found that the reverse transcriptase enzyme of HIV has parts, or domains, referred to as "fingers," "palm," "thumb," and "connection." These are used by the enzyme to seize hold of the nucleotide in much the same way that a human hand grasps an object.
"If you hold your hand out with the palm cupped, that's a crude description of the overall shape of the protein," Harrison said.
The HIV reverse transcriptase enzyme uses one particular nucleotide to copy its genetic material and start the victim cell down the road to becoming a miniature virus factory.
"We've captured this enzyme in the act of copying a viral gene," Harrison said. As it does this, the "fingers" curl in toward the "palm." Not only could Harrison's team see the process, they could see the changes in the amino acids that make up the protein that confer resistance to each drug.
"A major and annoying puzzle had been that we had been unable to understand why those particular mutations had conferred resistance," Harrison said. "It allows us to understand and rationalize the resistance."
Copyright© 1998 Reuters Limited.
