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Discovery pinpoints potential Achilles’ Heel in HIV, opening new frontier in drug development
Scientists have long known that detecting HIV early is crucial in slowing and treating the virus. During the acute stage of infection, a single human cell can produce as many as 10,000 new HIV particles. A discovery led by the University of Delaware's Juan Perilla offers hope: A new drug target early in the virus's life cycle that could save millions of lives. In the surprising discovery, published Feb. 18 in Nature, Perilla and collaborators in the U.S. and the United Kingdom, have revealed a previously unknown role for the viral protein integrase. Scientists already knew that integrase helps HIV insert itself into human DNA. But this new study provides the first direct evidence that integrase plays a critical structural role earlier on in HIV’s life cycle — when the virus matures into an infectious force. Using high-resolution cryo-electron microscopy (cryo-EM), the research team – which also included UD doctoral student Juan S. Rey – found that integrase proteins form gluey filaments that line the inside of the capsid. Each segment of the filament slots neatly into the capsid’s hexagon-shaped tiles, while gripping tightly to HIV’s RNA genome. This zipper-like arrangement organizes and packs the virus, preparing it to hijack a cell and start making copies of itself. “Integrase plays a structural role inside the HIV capsid — nobody expected that,” Perilla said. “This protein forms filaments that anchor the RNA to the capsid. Without these filaments, the virus is non-infective.” Seeing inside HIV is no small feat. The capsid is only about 120 nanometers wide —roughly 1/800th the thickness of a human hair. It is incredibly small, fragile, densely packed and constantly changing, Perilla said. To reveal its hidden architecture, the researchers relied on deep collaboration and a combination of sophisticated microscopy, molecular modeling and experimentation. Read more about the science behind the study here. “The thing with HIV is that people are chronically living with it,” Perilla said. “Treatments are effective, but patients always need new therapeutics. We want to help develop the next generation of inhibitors and hope to have a significant contribution.” To reach Perilla directly and arrange an interview, visit his profile page. Interested reporters can also email MediaRelations@udel.edu.
