12/23/2002 08:00:00

Caltech, UCLA Researchers Create a New Gene Therapy for Treatment of HIV

PASADENA, Calif.— California Institute of Technology and UCLA researchers have developed a new gene therapy that is highly effective in preventing the HIV virus from infecting individual cells in the immune system. The technique, while not curative, could be used as a significant new treatment for people already infected by reducing the HIV-infected cells in their bodies.

Also, the new approach could be used to fight other diseases resulting from gene malfunctions, including cancer.

Reporting in the current issue of the Proceeding s of the National Academy of Sciences (PNAS), Caltech biologist David Baltimore and his UCLA collaborators announce that the new technique works by using a disabled version of the AIDS virus as a sort of "Trojan horse" to get a disruptive agent inside the human T-cells, thereby reducing the likelihood that a potent HIV virus will be able to successfully invade the cell. Early laboratory results show that more than 80 percent of the T-cells may be protected.

"To penetrate a cell, HIV needs two receptors that operate like doorknobs and allow the virus inside," says Baltimore, who is president of Caltech. "HIV grabs the receptor and forces itself into the cell. If we can knock out one of these receptors, we hope to prevent HIV from infecting the cell."

The receptors in question are called the CCR5 and the CD4. The human immune system can't get along without the CD4, but about 1 percent of the Caucasian population is born without the CCR5. In fact, these people are known to have a natural immunity to AIDS.

Therefore, the researchers' strategy was to disrupt the CCR5 receptor. They did this by introducing a special double-stranded RNA known as "small interfering RNA," or siRNA, into the T-cell. To do so, they engineered a disabled HIV virus to carry the siRNA into the T-cell. Thus, the T-cell was invaded, but the disabled virus has no ability to cause disease. Once inside the T-cell, the siRNA knocks out the CCR5 receptor.

Laboratory results show that human T-cells thus protected are then quite resistant to infection by the HIV virus. When the T-cells were put in a petri dish and exposed to HIV, less than 20 percent of the cells were actually infected.

"Synthetic siRNAs are powerful tools," says Irvin S.Y. Chen, one of the authors of the paper and director of the UCLA AIDS Institute. "But scientists have been baffled at how to insert them into the immune system in stable form. You can't just sprinkle them on the cells."

The other two authors of the paper are Xiao-Feng Qin, a postdoctoral researcher at Caltech; and Dong Sung An, a postdoctoral researcher at UCLA. The two contributed equally to the work.

The technique should become a significant new means of treating people already infected with HIV, Baltimore and Chen say.

"Our findings raise the hope that we can use this approach or combine it with drugs to treat HIV in people—particularly in persons who have not experienced good results with other forms of treatment," says Baltimore.

The technique can also potentially be used for other diseases when a specific gene needs to be knocked out, such as the malfunctioning genes associated with cancer, Chen says. "We can easily make siRNAs and use the carrier to deliver them into different cell types to turn off a gene malfunction," he says.

In addition, the technique could be used to prevent certain microorganisms from invading the body, Baltimore adds.

The research is supported by the National Institute of Allergy and Infectious Diseases and the Damon Runyon-Walter Winchell Fellowship.

[Note to editors: UCLA is also issuing a news release on this research. Contact Elaine Schmidt at (310) 794-2272; elaines@support.ucla.edu]

Written by Robert Tindol