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Scientists Develop Effective HIV siRNA Delivery System

NEW YORK (GenomeWeb News) – Small interfering RNA delivered directly to immune cells can suppress the human immunodeficiency virus in animal models of the disease, new research suggests.
 
In a paper appearing online today in Cell, an international team of researchers demonstrated that they could thwart HIV in mouse models by delivering interfering RNAs to T-cells — a type of immune cell that’s typically ravaged by the virus. By silencing just three genes, the team protected these cells from much of the damage normally associated with HIV infection, offering hope that researchers may eventually develop effective siRNA-based HIV therapies for humans.
 
Small interfering RNAs can bind to messenger RNA and prevent its translation, which offers the possibility that siRNAs could be used to disable the molecules behind HIV and other diseases. Indeed, several studies have shown that siRNAs can curb HIV replication in cultured cells.
 
But finding an effective strategy for delivering siRNA to the proper site in real-life systems has remained problematic — as has a lack of appropriate HIV animal models. “Animal models for HIV-1 have suffered from either the lack of a system that precisely mirrors human HIV infection or, in the case of primate models, scarcity of species, high cost, and the need to use the related but distinct simian virus for infection,” the authors noted.
 
To overcome the animal model problem, several labs have been working on immuno-deficient mice that can be transfused with human T-cells and/or stem cells, lead author Priti Kumar, an instructor and post-doctoral research fellow at Harvard University Medical School’s Immune Disease Institute and Department of Pediatrics, told GenomeWeb Daily News.
 
For this study, the researchers used a new mouse strain, developed by co-authors Leonard Shultz, a researcher at the Jackson Laboratory, and University of Massachusetts researcher Dale Greiner, that can be transplanted with human immune cells or human stem cells that subsequently generate a human immune system in the animals.
 
Next Kumar and her co-workers had to come up with a way to deliver the siRNAs to T-cells. Because they are recalcitrant to the uptake of nucleic acids, Kumar said, the T-cells need to be coaxed to take up the molecules. Attaching them to an antibody against a T-cell surface protein is one way of doing this. After the antibody-siRNA complex binds on the cell surface, it is taken up by endocytosis, delivering the antibody and its cargo into the cell.
 
Another notorious problem facing HIV researchers: rapid viral mutation. In an effort to prevent viral escape variants, the researchers targeted not one but three different sequences: the sequences coding for CCR5, a human T-cell surface protein used by HIV to get into the cells, and two well-conserved HIV proteins.
 
When they used this antibody-siRNA cocktail to treat immune-deficient mice containing HIV-negative human T-cells, the team saw dramatic results. Whereas control mice and mice given other siRNAs lost T-cells as early as ten days after HIV infection, three out of four mice that were given the therapeutic siRNAs had T-cell profiles that were essentially like those of non-HIV mice.
 
And in the fourth mouse, the T-cell decline appeared to be less precipitous than usual, suggesting that this animal also received some protection from the treatment.
 
The RNAi cocktail also suppressed HIV in mice transfused with HIV-positive T-cells from peripheral blood of patients receiving highly active antiretroviral therapy (HAART). In the mice treated with the antibody-siRNA concoction T-cells expanded. On the other hand, control mice again exhibited T-cell depletion within ten days or so.
 
To determine whether the treatment was also effective over longer time periods, the researchers then tested it in mice with reconstituted human immune systems — those engrafted with human stem cells derived from cord blood. “We were totally able to stop [HIV] infection in these mice as well,” Kumar said.
 
The antibody-siRNA treatment isn’t ready for clinical trials yet, she emphasized. First, researchers need to verify the results in other animal models and determine the optimal dose and treatment frequency. They may also need to consider other issues related to toxicity and siRNA delivery, she added. For example, the team used a mouse antibody for this study, Kumar noted, but it’s possible that the same antibody would produce an unwanted immune response in humans.
 
Even so, the results are promising and may eventually lead to new treatments to augment HAART. That treatment, while extremely useful, Kumar said, still suffers from problems such as high toxicity in some patients and the emergence of resistant mutants.
 
“This is nice proof of principle that [siRNA treatment] could be used as a therapeutic strategy,” senior author Premlata Shankar, formerly of Harvard University Medical School and now at the Texas Tech University Health Sciences Center, said in a statement. “We think it has real promise, but there is a lot more to be done.”
 
 

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