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Providing Answers About Viruses and Drug Resistance

Dr. Kovari demonstrates the HIV protease which is critical to viruses and drug resistance.

One of the reasons HIV is so difficult to treat is the virus’ ability to change. Even the most successful drug treatments all too quickly become ineffective as the virus mutates and regains its foothold. Ladislau Kovari, PhD, assistant professor of biochemistry and molecular biology, believes he now understands how the virus develops its drug resistance — information that could help in the design of new pharmaceuticals that can defeat the resistant viral forms.

“Patients start out taking the anti-retroviral cocktail that usually includes one protease inhibitor and two reverse-transcriptase inhibitors,” he began. At first, the amount of circulating virus, or the “viral load,” drops to undetectable levels, which means the treatment is effective. “However, over time, the viral load starts increasing. Usually this is an indication of one of two things: the patient isn’t adhering to the medication schedule, or resistant forms of the virus are starting to emerge.”

Dr. Kovari is especially interested in how the virus changes to develop resistance, and has developed a novel hypothesis that centers on the HIV protease, a viral enzyme that the drug targets. “One can think about the HIV protease and the drug as lock and key. The key is the drug and the lock is the protease,” he explained. When the key is in the lock, the enzyme shuts down and the virus can’t function properly. “What we think is happening is that, as the virus mutates, the active site of the HIV protease expands, and the binding of the drug to the active site becomes loose. In other words, the lock keeps expanding and therefore the key doesn’t fit as well.” At that point, the drug loses its effectiveness.

To test this hypothesis, he and his research team have obtained four multi-drug resistant HIV clinical isolates sent by their collaborators at Stanford University. Using X-ray crystallography and molecular modeling techniques, they are meticulously examining three-dimensional views of HIV protease-drug complexes so they can pinpoint which interactions between the drug and the protease are lost as the virus becomes resistant.

“The next logical step would be to redesign the drug. Thus, one can think of designing a larger drug that fits with the expanded size of the HIV protease active site and that is expected to be effective against the resistant forms of the virus,” Dr. Kovari said. “That’s the practical application of the work.”

Dr. Kovari’s work receives funding through a three-year, $504,000 grant from the National Institutes of Health.

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