- A new treatment for HIV has been revealed
which uses the virus itself to select and trigger the death of infected
cells.
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- Crucially the gene therapy leaves healthy
cells alone.
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- It is also the first use of a biomolecular
technology which can smuggle large proteins into cells, a vital requirement
in gene therapy.
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- Experts have welcomed the treatment.
"It is a very elegant strategy in which the HIV induces cell suicide,"
said Dr Guiseppe Pantaleo at the University Hospital of Lausanne, Switzerland.
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- He told BBC News Online: "It also
selectively targets the infected cells, unlike currently used drugs."
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- The new drug has not yet been tested
in patients. But Dr Pantaleo said: "All gene therapies need more experiments
to prove their clinical worth. But if these researchers continue their
success we may see something in three or four years time."
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- Dr Pantaleo believes all strategies for
treating HIV need exploring, partly because HIV could develop resistance
to existing drugs. "The new treatment will have very little chance
of producing resistance."
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- This is because it simultaneously uses
up to 10 molecular features of the virus. Scientists say it is "statistically
impossible" for all these features to mutate at the same time.
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- The gene therapy exploits HIV's reproductive
cycle to kill infected cells. The virus uses a protein called a protease
as scissors to cut out the enzymes it needs to replicate itself.
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- Current drugs sit in the hinge of the
scissors, preventing them closing but can become ineffective if the protease
mutates to a different shape.
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- However the new treatment tricks the
HIV protease into cutting different enzymes out of a drug molecule. These
enzymes causes the cell to self-destruct.
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- To make the drug molecule, researchers
at the Washington University School of Medicine had to fuse together a
brand new protein, TAT-Casp3.
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- They joined a protein piece that can
slip through cell membranes with two pieces of a human enzyme called caspase-3.
When activated, caspase causes cells to commit suicide. They then added
"cut-here" molecular markers to show the HIV protease where to
cut out the caspase.
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- In their experiments, TAT-Casp3 successfully
wormed its way into HIV infected cells and was then cut open by the viral
protease. This freed the caspase and resulted in the infected cells dying
in a few hours. HIV-free cells were not affected as they did not contain
the protease "scissors".
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- The TAT-Casp3 treatment is the first
to rely on a new technology that allows large proteins, hundreds of times
bigger than conventional drugs, to cross cell membranes. The key is that
the TAT protein unfolds before crossing the membrane, then re-folds once
inside the cell. In this case it is used to carry the useful caspase enzymes
into the cell.
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- "This Trojan horse approach should
be applicable to many other infectious diseases, such as hepatitis C, malaria
and herpes," said Dr Steven Dowdy, who led the research. Dr Dowdy
is also developing a fusion protein that aims to kill prostate cancer cells.
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- One advantage of using large proteins
as medicines is that, unlike small drugs, they fit only onto the molecules
for which they were designed. They could therefore be given in substantially
lower doses and should cause fewer side effects.
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- A second new treatment was also announced
in the journal Nature Medicine. It tackles the idea that HIV thrives because
the body's immune system has too few "killer T cells", which
would normally destroy the virus.
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- The researchers, also at the Washington
University School of Medicine, injected HIV-positive patients with additional
killer T cells. These had been genetically engineered so they could be
tracked in the body.
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- The cells successfully sought out and
killed HIV-infected cells in the lymph nodes, suggesting that this therapy
could boost the ability of infected people to fight the virus.
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- However, Dr Pantaleo told BBC News Online:
"It does home in on where the virus is, proving a point, but I think
this has a very small chance of working clinically. It is difficult to
make killer T cells, they need to be injected every day and they have rather
minimal effect anti-viral effect."
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