From Our 2008 Archives
Font Size
A
A
A

Gene Silencing May Stop AIDS Virus

Study Shows New Technique Has Potential as AIDS Therapy

By Daniel J. DeNoon
WebMD Health News

Reviewed By Louise Chang, MD

Aug. 8, 2008 — A new gene silencing technique stops HIV cold in mouse studies and promises to become a potent new AIDS therapy with few side effects.

The technique uses short interfering RNA, also called silencing RNA or siRNA. These tiny snips of RNA are designed to stick to specific genes, which are then rendered inoperative or "silent."

Researchers have previously shown that siRNA aimed at HIV can shut down the AIDS virus in the test tube. It can also target the T cells HIV loves to infect, shutting the window through which HIV enters.

Now Priti Kumar, PhD, Premlata Shankar, MD, and colleagues have linked siRNA to an antibody that delivers them directly to T cells — and to a molecule that transports them to the cell nucleus where it can attack HIV genes.

They used a siRNA cocktail: two siRNAs that inactivate different HIV genes and one siRNA that keeps T cells from expressing the CCR5 molecule to which HIV attaches.

"In mice pre-treated with the siRNA cocktail and then infected with HIV, we could not find any signs of virus for a long period of time," Kumar tells WebMD. "And when we treated mice whose immune systems had been reconstituted with T cells from an HIV infected individuals, they were totally able to block expansion of the virus."

Working in Shankar's Harvard lab (recently moved to the Texas Tech Health Sciences Center), the researchers used recently developed mouse models of HIV infection. In these models, immune-deficient mice have their immune systems reconstituted either with adult human T cells or with human stem cells that provide a continuing source of T cells.

"You get a mouse with the immune system of a human," Kumar says.

This mouse model is a big advance in the development of new AIDS treatments, says longtime AIDS researcher Margaret Fischl, MD, director and principal investigator of the AIDS clinical research unit at the University of Miami.

"The humanized mouse model is very interesting," Fischl says. "It would give me much more information on the effectiveness and toxicity of treatments and save time in human clinical trials."

Fischl has seen a lot of promising AIDS therapies come and go, but she finds the siRNA approach "intriguing" and would like to see it explored further.

One of the researchers doing this exploration is Ramesh K. Akkina, PhD, professor of microbiology, immunology, and pathology at Colorado State University, Fort Collins.

"The Shankar lab's finding is certainly an exciting development," Akkina tells WebMD. "This siRNA is a very interesting molecule that is actually programming cells to deal with the virus."

Akkina notes that the Shankar/Kumar team is using direct injections of siRNA constructs, an approach to gene therapy thatwould require repeat administrations. Another approach uses a genetically engineered virus that infects blood-forming stem cells and becomes a permanent part of their genome. When these stem cells become T cells, they produce siRNA and are immune to HIV infection.

"In the approach with the stem-cell gene-therapy approach, we are programming blood-forming stem cells with anti-HIV siRNA so that the stem cells are viable lifelong in the individual," Akkina says. "The virus-resisting cells are produced on a daily basis."

Sponsored by Benitec, the firm developing this approach, a phase I safety study of virus-delivered siRNA is under way at City of Hope Medical Center in Duarte, Calif.

Kumar says her team's approach would avoid the pitfall of having a foreign virus integrate into the human genome.

Both approaches hold promise for reaching the so-called "resting" T-cells in which HIV is able to hide from current AIDS therapies. Reaching these HIV reservoirs is the key to eliminating HIV from the body.

"These approaches could be used to purge the latently infected cells," Akkina says.

Kumar agrees.

"The advantage of siRNA is that you can deliver it into resting T cells," she says. "So if these siRNA are present when the cell becomes activated and starts to produce HIV, you have siRNA there ready to combat it."

Kumar and colleagues report their findings in the Aug. 22 issue of the journal Cell. Kumar, an instructor at Harvard Medical School while working in the Shankar lab, is now an assistant professor at Yale University.

SOURCES: Kumar, P. Cell, Aug. 22, 2008; vol 134: pp 1-10. Benitec web site. Priti Kumar, PhD, assistant professor, Yale University. Margaret Fischl, MD, director and principal investigator, AIDS Clinical Research Unit, University of Miami. Ramesh K. Akkina, PhD professor of microbiology, immunology, and pathology, Colorado State University, Fort Collins.

©2008 WebMD, LLC. All Rights Reserved.








Medical Dictionary