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Sat, 3 Dec 2011 01:45:04 -0500
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Gene Therapy Can Protect Against HIV

     An introduced gene conveys long-lived resistance to
     HIV infection in mice.

Lauren Gravitz
Nature
30 November 2011
http://www.nature.com/news/gene-therapy-can-protect-against-hiv-1.9516

Gene therapy, an approach most commonly explored for
curing chronic genetic diseases such as cystic fibrosis,
may also prove practical for disease prevention. In
research published today in Nature[1], scientists in
California show that a single injection - which inserted
the DNA for an HIV-neutralizing antibody into the muscle
cells of live mice - completely protected the animals
against HIV transmission.

The road to a vaccine against HIV has proved to be far
longer than originally anticipated. More than 2 million
adults are newly infected with HIV every year and,
nearly three decades after the virus was first
identified, researchers haven't found a reliable way to
prevent infection. The classic vaccine approach, which
uses all or part of an inactivated virus to induce
immunity, has yielded little success because HIV has
managed to disguise most of the easily-recognised
external structures that antibodies would target.
Researchers have thus had a tough time finding a
molecule that can induce even moderately broad responses
against the virus in all its different mutations. So
although it might sound extreme to use gene therapy as a
preventative treatment for HIV/AIDS, the method could
provide a much-needed alternative.

David Baltimore, a virologist and HIV researcher at the
California Institute of Technology in Pasadena, and his
colleagues used a genetically altered adenovirus to
infect muscle cells and deliver DNA that codes for
antibodies isolated from the blood of people infected
with HIV. The DNA is incorporated into the muscle cells'
genome and programs the cells to manufacture the
antibody, which is then secreted into the bloodstream.
The tactic builds on earlier work by scientists at the
Children's Hospital of Philadelphia in Pennsylvania, who
in 2009 first described the effectiveness of this
technique in preventing transmission of simian
immunodeficiency virus, which is similar to HIV but
infects monkeys[2].

As for the rationale for using gene therapy for HIV:
"This is something way out of the ordinary, and it's
perfectly reasonable to say that there's no reason to do
it if there's an alternative," says Baltimore. "But if
there's no alternative - and that's where we're at today
- then we should be thinking of new ways to protect
people."

Dennis Burton, an immunologist at the Scripps Research
Institute in La Jolla, California, who has developed a
number of antibodies against HIV, agrees. "Obviously,
the best thing of all is a vaccine. That's a tried-and-
tested method that carries very few risks. But if that
doesn't work, what's our fall-back position?" he asks.
"We have these antibodies, and we have them available
now. If this works in humans, and that's a reasonable
supposition, you'd have something you can do now."

Prolonged protection

Baltimore and his colleagues tested five different
broadly neutralizing antibodies, one at a time, in mice
with humanized immune systems. Two of the antibodies,
called b12 and VRC01, proved completely protective -
even when the mice received doses of HIV that were 100
times higher than a natural infection. After 52 weeks,
the levels of antibody expression remained high,
suggesting that a single dose would result in long-
lasting protection. "We showed that you can express
protective levels of antibodies in a mammal and have
that expression last for a long period of time,"
Baltimore says. "It sets the stage for human trials."

Providing patients with periodic doses of these
antibodies throughout their lifetime would be safer than
coaxing antibody production from muscle cells, but it
would be far from cost-effective. The gene-therapy
approach, by contrast, recruits muscle cells to act as
antibody factories and could be administered using a
single intramuscular shot.

Experts in the field are cautiously optimistic. "Mice
and monkeys don't always tell the truth. It's a really
interesting idea, and it should be assessed in clinical
trials," says Wayne Koff, senior vice-president for
research and development at the International AIDS
Vaccine Initiative in New York. "Until someone shows
that we can make these broadly neutralizing antibodies
with a [classic] vaccine, I think this is an important
concept that should be supported."

But both Burton and Koff caution that gene therapy comes
with its own set of problems. Because the antibody DNA
is permanently inserted into the genome, there's no way
to turn it off if someone has an immune reaction against
the antibodies. But it won't be known whether such side
effects exist until the method is tested in people,
something that Baltimore aims to do in the next few
years. The researchers at the Children's Hospital of
Philadelphia, meanwhile, hope to get the first round of
human trials of their technique started before the end
of 2012.

Nature doi:10.1038/nature.2011.9516

References

1 Balazs, A. B. et al. Nature advance online publication
http://dx.doi.org/10.1038/nature10660 (2011).

2 Johnson, P. R. et al. Nature Med. 15, 901-906 (2009).

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