New HIV Therapy Tricks
Infected Cells Into Suicide
BBC News Sci/Tech
A new treatment for HIV has been revealed which uses the virus itself to select and trigger the death of infected cells.
Crucially the gene therapy leaves healthy cells alone.
It is also the first use of a biomolecular technology which can smuggle large proteins into cells, a vital requirement in gene therapy.
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.
He told BBC News Online: "It also selectively targets the infected cells, unlike currently used drugs."
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."
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."
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.
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.
Current drugs sit in the hinge of the scissors, preventing them closing but can become ineffective if the protease mutates to a different shape.
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.
To make the drug molecule, researchers at the Washington University School of Medicine had to fuse together a brand new protein, TAT-Casp3.
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.
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".
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.
"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.
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.
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.
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.
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.
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."