In an attempt to fight fire with fire, researchers have engineered a virus that usually infects cattle to attack the AIDS virus in humans. "It's really on the verge of a breakthrough," says Nava Sarver, who oversees development of novel AIDS treatments at the National Institute of Allergy and Infectious Diseases (NIAID).
Yale University virologist John Rose and co-workers describe in tomorrow's Cell how they have constructed a potential HIV treatment by modifying vesicular stomatitis virus (VSV), which farmers detest because it causes a mouth infection in cattle that prevents them from eating. As the Yale researchers' test-tube experiments show, their new-fangled VSV selectively targets and destroys HIV-infected human cells. "It's a pretty interesting way of harnessing a virus for peaceful purposes," says the University of Pennsylvania's Robert Doms, whose lab has helped elucidate how HIV infects cells. "It's a very clever approach."
The work takes advantage of recent discoveries made by Doms and others about a two-part handshake between HIV and the cells it infects. After HIV binds to the CD4 receptor on a white blood cell, it also must link to another molecule found on the cell's surface known as a chemokine receptor. Once these handshakes are complete, HIV gains entry. Shortly thereafter, pieces of the virus make their way to the cell's outer coating where they stick out of the cell like a flag of victory.
Rose and colleagues reasoned that if they could stitch into VSV the genes that code for CD4 and one of HIV's favored chemokine receptors, CXCR4, the virus would home in on cells that have these HIV flags sticking out of them. The HIV proteins on the surface of the infected cell, they surmised, would bind to the VSV's CD4 and CXCR4 receptors. When the researchers added their engineered VSV to a culture containing HIV-infected cells, they found that it did indeed target just the infected cells, killing them rapidly. "VSV is so fast," says Rose, noting that it can kill cells much more quickly than can HIV.
A potential downside to this approach is the possibility that the modified VSV will kill cells that aren't infected by HIV. Rose believes that won't happen because he has stripped VSV of its own surface protein, which is what allows it to infect a broad range of cells. "Without its normal coat, it can't infect anything," says Rose. But only animal tests will answer that question, cautions NIAID director Anthony Fauci. Although Fauci has high praise for the novelty of the concept, he also is concerned that it might take infusions with a impractically high dose of the modified VSV to impact a person's HIV levels.
Still, Sarver, Fauci, and others are anxious for Rose and colleagues to put their viral guided missile to more stringent test-tube and animal tests. NIAID's Sarver suggest that if researchers indeed can swap different receptors into this "gutted" VSV, it may allow for precision targeting that could be used in everything from vaccines to gene therapies to cancer treatments. "We're not there yet," says Sarver, "but the potential applications are enormous."