New Milestones on the Path to Conquering HIV Drug Resistance

HIV is a moving target, unpredictably changing direction to elude anti-AIDS drugs, but researchers at Rutgers are clearly on the track of solutions to combat HIV drug resistance. Leading a multidisciplinary ensemble of colleagues, Rutgers Chemistry Professor Eddy Arnold (pictured at right) has published three reports on studies that revealed how some drugs may be getting the better of the virus' molecular defenses.

Tenofovir and the DAPY (diarylpyrimidine) compounds are different types of reverse transcriptase (RT) inhibitors. RT is the enzyme or molecular machine the AIDS virus uses to replicate its genetic material. The two life-saving drugs approach the problem of drug resistance in different ways.

Arnold, a resident faculty member of the Center for Advanced Biotechnology and Medicine (a research institute jointly administered by the University of Medicine and Dentistry of New Jersey and Rutgers), and his colleagues work on drugs that target HIV RT.

HIV RT uses ingredients available within the cell as building blocks to make the genetic copies that allow the virus to proliferate. These building blocks or substrates are fitted together to create new copies of the viral genetic information.

Arnold's team concludes that tenofovir - on the market as Viread from Gilead Sciences - is relatively effective in evading HIV resistance because it's "lean and mean." The tenofovir molecule is slightly smaller than the normal building blocks, which enables it to substitute for those the RT is trying to use. Because tenofovir is smaller, it is difficult for RT to learn to distinguish it from the normal building blocks and develop resistance to the drug.

The interpretation provides insight into one mechanism of drug resistance, but the researchers also explored another mechanism displayed by the DAPY family of compounds. The DAPY compounds employ another mechanism, attaching themselves to a site near the heart of the RT molecular machine and blocking its activity. "It's like throwing a molecular monkey wrench into the virus's essential machinery," Arnold said. The success of the compounds may be due to their ability to assume different shapes, allowing them to adapt to the changing shapes found in the virus's repertoire of drug-resistant forms. Arnold describes the DAPY antics as "rolling with the punches, wiggling and jiggling around until they fit the particular RT configuration."

"The conclusions we have drawn do not represent an endpoint, but rather punctuation marks - places where we have achieved some significant milestones that will help guide us in the design of new and more effective anti-AIDS drugs," Arnold said.