The Gag Machine

David Pacchioli
June 01, 1995

A virus works by invasion and takeover. Once it gains entry, the viral particle commandeers a cell's reproductive apparatus to make more of itself. New-minted particles migrate to the cell wall and push through it, pinching off to freedom in a process called budding. Then away they swim in search of new cells to conquer.

In retroviruses, including the AIDS virus HIV, control over budding falls to the gag gene.

John Wills demonstrated this five years ago. Wills, associate professor of microbiology and immunology at Penn State's Hershey Medical Center, was working with Rous sarcoma virus (RSV), a retrovirus that causes tumors in chickens. If he snipped the gag gene from RSV, he found, and plunked it into a cell, it would bud new particles of a denatured strain of RSV. The process worked with mammal cells as well as avian ones, and Gag (for "group specific antigen," the protein the gene codes for) was all you needed. "It's a particle-making machine," Wills says.

Discovering this fact meant he suddenly had the ability to make viral particles in large numbers, easily and—since RSV does not infect humans—safely. Wills remembers wondering: "Can we take advantage of this?"

He conceived of a way to incorporate foreign proteins into his mass-produced RSV particles, by fusing the appropriate genes onto the gag gene. In effect, what he found was a way to gift-wrap a protein for delivery into a cell.

Wills' gift-wrapping process, since patented, holds great promise for the development of vaccines. Connaught, a major drug manufacturer, has licensed the technology for use in an AIDS vaccine.

As Wills explains, there is evidence, in long-term AIDS survivors—people who have lived for up to 15 years with the disease—that some people's immune systems battle HIV effectively. "If we can find out how to tickle the immune system in the right way," he says, by determining which proteins or epitopes in HIV elicited the immune response in these survivors, it might be possible to create a vaccine.

With Wills' technique, one could take RSV, a safe, dead virus, and engineer just the proper HIV epitopes into it, leaving out HIV's RNA and other dangerous components.

But what most excites him, Wills says, is the continuing effort to understand how Gag works—to find the pieces of the machine.

"We're stripping it down to the chassis. It's like taking a car engine and trying to figure out what's essential by throwing out one piece at a time."

If Wills and his team can elucidate the exact mechanism of budding in RSV, it could lead to a whole new approach in the fight against HIV.

"Lots of work has been done on drugs whose object is to block the virus from entering the cell, like AZT," Wills explains. "They're not working."

Using Gag, the object would be instead to try to prevent the virus from leaving the cell once it gets in—stop it from spreading. If they could understand the assembly process well enough, Wills believes, he and his colleagues could design a "monkey wrench" that might shut the Gag machine down.

John W. Wills, Ph.D., is associate professor of microbiology and immunology in the College of Medicine, The Milton S. Hershey Medical Center, Pennsylvania State University, 500 University Drive, Hershey, PA 17033; 717-531-3528.

Last Updated June 01, 1995