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'Smart Bomb' RNA Molecule Could Take Out Drug-Resistant HIV

RNA dynamic duo curbs infection in mice.

By Cassandra Willyard

An RNA molecule engineered to attack HIV in two different ways is showing positive results, according to a study in Science Translational Medicine. The researchers say that the molecule, which both curbs viral replication inside infected cells and neutralizes free-floating virus, could help patients who have developed resistance to HIV drugs.

The molecule, known as a chimaera, is composed of two different types of RNA: a small interfering RNA (siRNA), designed to enter infected cells and block the expression of two genes that HIV needs to replicate, and an RNA sequence known as an aptamer, which binds tightly to gp120, a protein found on the surface of HIV and HIV-infected cells. The aptamer has a dual role: it ferries the siRNA into infected cells and it neutralizes free-floating virus in the blood.

John Rossi, a molecular biologist at the Beckman Research Institute of the City of Hope in Duarte, California, a lead author on the paper, describes the molecule as a smart bomb. "You're only targeting what has to be targeted," he says.

The chimaera is not new, but this is the first time it has been tested in animals. To test the chimaera, the team used mice engineered to be susceptible to HIV. When the researchers injected mice with either the chimaera or the aptamer alone, the amount of virus circulating in the animals' blood fell markedly. The chimaera, however, was more potent and suppressed the virus for a week longer than just the aptamer.

Rossi says that the molecule could be used as a stand-alone therapy, or in combination with other drugs that treat HIV. Because the antiviral effect of the chimaera lasts only about a week, patients would need to have regular injections.

Not pulling its weight

"This molecule, this design, is beautiful," says Ben Berkhout, a retrovirologist at the University of Amsterdam. But he is not entirely convinced that the siRNA has much of an impact. "They do see quite dramatic inhibition" of HIV, he says. But most of that inhibition seems to be due to the aptamer, not the siRNA. "I haven't seen the double action of this combination," he says.

The researchers found the siRNA in white blood cells known as lymphocytes of mice treated with the chimaera, indicating that the molecule can get where it needs to be. And when they measured the expression of the two genes targeted by the siRNA--tat and rev--in those same cells, they found a 75-90% reduction in expression after treatment. They also saw that the siRNA was cleaving the tat and rev genes in the right spots, an indication that the molecule worked the way it was supposed to.

But Phillip Sharp, a molecular biologist at the Massachusetts Institute of Technology in Cambridge, says that although the study shows some siRNA activity in the lymphocytes of the mice, it "doesn't show that most of the lymphocytes have siRNA activity. The question is how effectively is the siRNA internalized and utilized."

Because the chimaera doesn't kill infected cells, it won't cure HIV. The next step, says Rossi, is to use a chimaera to deliver siRNAs that can kill infected cells. "What you want to do is start purging the infected cell population," he says.

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