HIV's Spread at Cellular Level Stopped by Indian-Origin Researchers

by Rajashri on Aug 9 2008 4:15 PM

A revolutionary technique that may suppress HIV's spread dramatically has been identified by an international team of researchers that included Indian origin scientists.

While working with mice infected with HIV, the researchers used a method called RNA interference to knock down three genes in T cells, protecting them from the virus.

They say that this method seemed to prevent HIV from jumping between cells in the mice.

"For the first time, we've used RNAi to dramatically suppress HIV infection in an organism," said co-author Premlata Shankar, who conducted the work while she was a junior investigator at the Harvard Medical School-affiliated Immune Disease Institute and an assistant professor at Harvard Medical School.

The discovery raises the possibility of a treatment for HIV that does not involve potentially toxic anti-viral drugs.

In collaboration with Sang-Kyung Lee of Hanyang University, Shankar's lab delivered RNAs (siRNAs) - molecules that silence genes by disrupting the protein templates they produce - directly into T cells, which are targeted by HIV.

Researchers used an apparatus analogous to a truck equipped with GPS and a trailer hitch to haul the siRNAs to their destination.

The truck, in this case, a single-chain antibody developed by Georg Fey of the University of Erlangen in Germany, homed to a protein found exclusively on the surface of T cells.

The trailer hitch, an oligo-9-arginine, pulled siRNAs along for the ride. This new antibody delivery vehicle lends itself to mass production in a dish.

Researchers built thousands of these carriers for use in experiments, loading them with siRNAs targeting three key genes.

One encodes a human protein called CCR5, which dots the surface of T cells and allows HIV to gain entry. The others encode proteins produced by the virus within cells upon infection.

Priti Kumar, Harvard Medical School postdoctoral researcher and first author, mixed the siRNAs with the antibody carriers and injected them into the veins of mice that harbor human T cells rather than their own.

These mice serve as an animal model of HIV. After being infected with the virus, the mice mirror progression of the disease in humans.

Researchers injected the mice with human blood stem cells, which divided time and again, building a human immune system in their hosts.

When infected with HIV, the synthetic immune system seemed to respond as it would in humans, since T cell levels followed the same pattern in both species.

Kumar's siRNAs halted T cell destruction in the mice, essentially stopping the virus in its tracks.

"Both prophylactic and therapeutic regimens proved successful. Apparently, the siRNAs kept HIV from entering most T cells and kept it from replicating when it managed to slip inside," said Kumar.

Kumar and Shankar caution that labs need to confirm the findings in other animals, tweak the dosage, and tinker with the siRNA delivery vehicle before attempting clinical trials.

"I'm not saying we've developed tomorrow's therapy, but this is a major step forward. We've used a small animal model for HIV and proven that RNAi works in that model," Shankar said.

The study is published online Aug. 7 in Cell.