United Press International - Tuesday, January 5, 1999
Ed Susman

If animal studies continue to show promise, protein therapy in humans could begin within two years, researchers at Washington University School of Medicine, St. Louis, said today.

"We are entering a brave new world of protein therapy that up till now we didn't know existed. This is the first example of protein therapy," said Steven Dowdy, assistant professor of molecular oncology whose work is funded by the Howard Hughes Medical Institute and the National Institutes of Health.

Dowdy told United Press International that until now pharmaceutical treatment of diseases was limited to small molecules which could penetrate the cell membrane. Small molecules have disadvantages: They don't get into every cell; they can be toxic to normal cells; they require large numbers; they are susceptible to development of resistance.

In 1988, Dowdy said scientists figured out how to unfold and refold larger proteins to allow these molecules to penetrate cells. But once it was shown to be possible, the work lay fallow, Dowdy said until he came up with the idea of using large proteins to attack HIV.

HIV, the virus that causes AIDS, uses a scissors-like protein called a protease to cut out enzymes it needs for reproduction. Drugs called protease inhibitors, which are extending many lives of HIV-infected people, sit in the hinge of the scissors, preventing the proteases from doing their job. But mutations in the protease can make the drugs ineffective. The drugs also inhibit a patient's own proteases, so they often are toxic.

Riding his bike to work one day, Dowdy thought, "Why not use the viral protease to kill the cell instead of using a drug to inactivate the protease?" Reporting in the January issue of the New York-based journal Nature Medicine, Dowdy and colleagues described how they designed a protein that would activate the system of programmed cell- death known as apoptosis. Once inside an HIV-infected cell, the HIV protease cuts the protein triggering capsace-3. Capsace-3 activation begins a robust, unstoppable chain reaction of thousands of capsace molecules in the cell, leading to cell death.

Dowdy said that in the test tube the reaction is so quick that all HIV-infected cells die within 10 minutes. "With protein therapy we can transduce -- get inside the cells -- 100 percent of the HIV-cells," he said. Because the protein molecule is programmed only to react to HIV- protease, uninfected cells are not affected. And because the reaction occurs so quickly and so far down the line of the cascade, Dowdy said he doesn't think the molecule will be able to develop a mutation to defend against the protein therapy.

"Even if it does somehow come up with a natural defense," Dowdy said the protein can be redesigned to attack that mutation as well. "This Trojan horse approach should be applicable to many other infectious diseases, such as hepatitis C, malaria and herpes," he said. "We also hope that future modifications will allow us to selectively kill cancer cells."

He cautioned, however, protein therapy is not a cure for AIDS. "We won't even begin human tests for at least a year," he cautioned. Animal studies are already under way.

Also in the issue of Nature Medicine, a research team at the University of Washington, Seattle, reported its work on a different therapeutic strategy to tackle HIV.

Scott Brodie and colleagues in the school's department of medicine based their research on the idea that HIV is able to thrive because of an insufficient number of the immune cells that would normally destroy the virus.

These cells are called CD8 cytotoxic T lymphocytes (CTLs), also known as killer T-cells. HIV-infected patients were injected with CTLs that were genetically engineered to carry a tracer molecule so that their location in the body could be monitored.

The CTLs migrated to the lymph nodes and killed HIV-infected cells. Brodie said this technique for augmenting the CTL capacity of infected individuals could be the basis of therapy for HIV.
990105
UP990101

Always watch for outdated information. This article first appeared in 1999. This material is designed to support, not replace, the relationship that exists between you and your doctor.

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1980, 1999. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content. .