Caltech, UCLA create HIV gene therapy

Researchers in the lab of Caltech president and professor of biology David Baltimore and at UCLA have developed a new gene therapy that is highly effective in preventing the HIV virus from infecting individual cells in the immune system.

While not curative, the technique 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.

In the current issue of the Proceedings of the National Academy of Sciences, Baltimore and his collaborators report that the technique uses a disabled version of the AIDS virus as a sort of “Trojan horse” to get a disruptive agent inside 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. “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 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 were actually infected.

“Synthetic siRNAs are powerful tools,” says Irvin S. Y. Chen, director of the UCLA AIDS Institute and one of the authors of the paper. “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.”

Caltech postdoctoral researcher Xiao-Feng Qin and UCLA postdoctoral researcher Dong Sung An are the paper’s other authors.

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, according to Chen. “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, Baltimore says, the technique could be used to prevent certain micro-organisms from invading the body.

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