Making T cells tougher against HIV

New study in mice shows RNA "scissors" adept at keeping the AIDS virus at bay

Normal 0 false false false MicrosoftInternetExplorer4 Normal 0 false false false MicrosoftInternetExplorer4 I pity the fool who messes with these T cells.

A method to deliver molecular “scissors” into T cells in mice makes the cells downright hostile to HIV. Not only do the cells reject the virus’s advances, but copies of the virus already inside the cells get snipped up.

The technique is the first to deliver these HIV-fighting scissors — called small interfering RNAs, or siRNAs — into T cells in living animals, Premlata Shankar of Texas Tech University Health Sciences Center in El Paso and her colleagues report in the Aug. 22 Cell. Shankar performed the research while at Harvard Medical School in Boston.

“I think they’ve shown very nicely that you can … target T cells and knock down the virus,” comments John Rossi, an AIDS researcher at the Beckman Research Institute at City of Hope in Duarte, Calif. “It’s a nice proof of principle that I think could be developed into a viable therapy.”

Previous research on cells grown in lab dishes showed that customized siRNAs can snip up the molecules that enable HIV to enter and subsequently kill T cells. Loss of these immune system cells leads to the immune deficiencies characteristic of AIDS.

In the new experiments, Shankar and her colleagues injected the custom siRNAs into mice that had their blood cells replaced with human ones. HIV can normally attack and kill human T cells in mice, but the siRNAs prevented loss of T cells due to the virus, the team reports.

“I think it could become a very good adjunct therapy,” Shankar says. “This would add to the arsenal.”

Existing HIV drugs also inhibit the virus from replicating inside T cells, and the health benefits of this new approach — if it’s ever approved for human use — would be similar. But unlike existing drugs, siRNAs are inherently flexible, so scientists could quickly adapt the siRNAs to target viral mutations that often make HIV resistant to conventional drugs.

An siRNA is a short molecule only 20 to 25 “letters” of genetic code long. If that code matches up with the sequence of letters in a gene, the siRNA will block the production of the protein coded by the gene.

Shankar’s team used an siRNA that targets the gene for a protein called CCR5. This protein sits on the outside surface of T cells. To enter the cells, most HIV variants must first bind to CCR5. So blocking the production of CCR5 slams the door on HIV. If it can’t enter the cells, HIV can’t replicate and hence kill the cells.

To deliver this siRNA — along with two others that target the genetic code of the virus itself — the researchers coupled the molecules to an antibody that targets a specific protein on the surface of T cells. When the siRNA-antibody pairs bind to this protein, called CD7, the cells swallow them.

The targeted delivery appeared specific enough to avoid toxic side effects, but more research to check for toxicity is needed, Rossi says. And the mouse antibody needs to be adapted for humans to prevent dangerous immune reactions.

Further tests on monkeys are needed before the treatment can be tested in human clinical trials, which would take several years to complete. If approved for people, the treatment would probably require weekly injections, Shankar says.

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