Scientists Now Know How
AIDS Virus Becomes
Resistant To New Drugs
By Maggie Fox
Health and Science Correspondent
Reuters News Service
WASHINGTON (Reuters) - Scientists said Thursday they had been able to "see" the changes that allow the AIDS virus become resistant to drugs and hope their images can help drug companies develop better ways to attack the virus.
Stephen Harrison and colleagues at the Howard Hughes Medical Institute at Harvard University were able to crystalize and make an image of the reverse transcriptase enzyme that HIV uses to replicate itself.
They caught the virus just after it attacked a cell and used an instrument known as a synchrotron, which is a high-intensity, high-energy X-ray crystallography machine, to record an image of the scene.
Reverse transcriptase is targeted by five HIV drugs now on the market, from the original drug, Glaxo-Wellcome's AZT, to Bristol-Myers Squibb's Videx.
They work by mimicking nucleotides, natural building blocks of DNA in the cell. These nucleotides are used by the HIV virus as it attacks a cell and injects its own genetic material into it, thus forcing the cell to pump out copies of virus instead of dividing naturally.
Such an approach has worked fairly well. Combined with drugs that attack the virus at a different stage of its cycle, known as protease inhibitors, the drugs can suppress the viral infection in many patients.
There is also a class of drugs known as non-nucleoside reverse transcriptase inhibitors (NNRTIs), which also affect reverse transcriptase but in different ways from the nucleoside mimickers, known formally as nucleoside-analog reverse transcriptase inhibitors.
But HIV eventually mutates in many people 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 will work together. Many fit together physically, like a lock and key.
Harrison's team confirmed that the virus mutates in specific ways that allow it to, in effect, 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.
The X-ray crystalography technique helped them to see the physical structures. "It allows you to see every amino acid, indeed every protein, in an atom," Harrison said in a telephone interview.
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 nucleoside much in the way a human hand grasps something.
"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 this process, they could see the changes in the amino acids that make up the protein that confer resistance to each drug.
"It allows us to understand and rationalize the resistance," he said. "A major and annoying puzzle had been ... that we had been unable to understand why those particular mutations had conferred resistance."
Now that they understand, he said, perhaps better drugs could be designed, and existing drugs could be used more effectively.