HIV knockout

A unique gene therapy technique could make immune cells resistant to HIV

Researchers may have found a way to give HIV the finger.

Removing immune system cells from mice and treating those cells with a custom protein called a zinc-finger nuclease in the lab made the cells resistant to HIV infection, scientists report online and in an upcoming Nature Biotechnology.

Injecting those cells back into the animals kept their viral load limited to less than one-tenth that in untreated mice and resulted in higher T cell counts among the treated animals. The technique could eventually provide a novel way to bolster the immune systems of people with HIV, which attacks T cells and uses them to replicate.

“We believe that by modifying T cells, we can provide an immediate benefit to patients,” says coauthor Philip Gregory, an expert in zinc-finger proteins and vice president of research at Sangamo BioSciences, a biotech company based in Richmond, Calif.

Zinc-finger nucleases — named for the zinc ions that hold the proteins together — act as scissors to snip DNA in specific places. Gregory and his colleagues designed a ZFN so that it would selectively disable the gene that encodes a specific protein on the surface of T cells. HIV uses this protein, called CCR5, as a doorway to invade the cells. Without CCR5, the most common form of HIV can’t infect the cells and thus can’t replicate.

To disable the gene, the researchers removed about a billion T cells from each mouse and exposed the cells to an adenovirus engineered to carry the genetic code for the customized ZFN.

The adenovirus delivered the ZFN gene into each cell’s interior, where the gene remained free-floating instead of integrating into the cell’s chromosomes — thus reducing the risk of cancer-causing mutations sometimes triggered by other kinds of gene therapy. Once inside the cell, the ZFN gene produced the ZFN protein, which in turn cut up the CCR5 gene.

After exposing the cells to the adenovirus, the scientists grew the cells in the lab until at least one of the two copies of the “HIV doorway” gene had been destroyed in about half of the cells.

These HIV-resistant cells constituted only a small fraction of a mouse’s total T cells after re-injection. But because HIV kills the T cells that it invades, unmodified cells get weeded out over time and the HIV-resistant cells multiply until they dominate the animals’ immune systems.

“This is an exciting result,” comments Carlos Barbas, a zinc-finger protein expert at the Scripps Research Institute in La Jolla, Calif. However, “I believe that CCR5 disruption will need to be accompanied by the addition of one or more [other] anti-HIV therapeutic genes” to make an effective therapy, he adds.

Gregory says that the technique could eventually be adapted for developing preventative vaccines, but research is needed first to demonstrate the safety of the approach. The researchers plan to begin clinical trials for this treatment later this year.

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