Mice have been made resistant to HIV by sabotaging a gene in the blood cells that the virus normally infects.

Researchers who developed the treatment at Sangamo BioSciences, a biotechnology company in Duarte, California, US, hope to test it in patients by the end of 2008. If successful, the treatment could offer a more effective way for controlling HIV in patients with the disease, the researchers say.

Once the gene has been altered, the cells can no longer make CCR5, a surface protein to which the virus attaches itself before sneaking inside. With no “door handle” to hold onto, the virus can no longer infect the cell.

To sabotage the gene that makes CCR5, they used a harmless virus to sneak a molecule called a zinc-finger nuclease into the cells.


Permanent change

The “zinc-finger” part of the molecule targets and binds exclusively to genetic material found only in the CCR5 gene. The “nuclease” section is an enzyme that snips open and alters the gene so that it can no longer make the CCR5 protein.

After this process, the cell is then effectively immune to infection by HIV. “Once the job is done, the cell DNA is altered permanently,” says Elena Perez at the Children’s Hospital of Philadelphia in Pennsylvania, who collaborated on the study.

Half the mice received human T-cells treated with the zinc-finger nucleases, and the other half received untreated T-cells. Later the mice were infected with HIV.

Inherited trait

After six weeks, all the treated mice had become resistant to the virus. “We saw a tenfold suppression of the virus in the treated mice compared with controls,” says Philip Gregory of Sangamo, “and we saw a five-fold increase in the number of circulating T-cells, [which are] usually attacked by HIV.”

In human trials, Sangamo plans to extract T-cells from HIV-infected patients, treat them in the lab to alter the gene that makes CCR5, then return them to the bloodstream.

The hope is that because these cells are resistant to HIV, as they multiply they will become the dominant type within the body. They could then provide longer-term protection than drugs that deny HIV access to cells by physically blocking CCR5 molecules.

“What’s really exciting is that the change in the genome is permanent, and inherited by all ‘daughter’ T-cells created when the altered T-cells multiply,” says Gregory.

Drug fallback

“The zinc-finger approach has significant potential compared to other strategies,” says Ed Berger, a researcher credited with helping establish the CCR5-HIV link at the National Institutes of Health in Bethesda, Maryland, US.

“With genetic knockout of CCR5 by the zinc finger, the cells lacking CCR5 have a selective advantage,” he says.

Berger adds that, unlike other approaches where patients have to carry on taking CCR5 blockers, or which depend on molecules that must continuously stop CCR5 working, the zinc finger only has to do one operation, and the job is complete.

John Moore, co-discoverer of the link between CCR5 and HIV in 1996, says the science is excellent, but doubts whether the gene can be sabotaged in enough T-cells to make a difference to patients.

He says that in any case, Maraviroc – a CCR5 blocking drug launched last year by Pfizer in the US and Europe – works well, and that others are in advanced clinical trials.

Journal reference: Nature Biotechnology (DOI: 10.1038/nbt1410)

HIV and AIDS – Learn more about the worst pandemic in human history in our continuously updated special report.