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.
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