Sense &
Antisense
In a special report from the cutting edge
of HIV treatment, Jeff Williams asks if genetically modified
HIV is the new HAART
Illustration Antonio Maggi
Results
from a small US study suggest scientists may have reached an important milestone
in developing what may well become the future of HIV therapy. Researchers
appear to have prevented HIV from reproducing inside CD4 cells using a genetically
modified version of the virus itself.
Biological revolution
DNA (deoxyribonucleic acid) is the chemical that makes all life possible.
It is at the heart of every cell in your body, controlling how they behave.
Scientists discovered its structure in 1952 triggering a revolution in biology.
One important realisation was the possibility of treating illnesses at a genetic
level.
Genes are sections of DNA that give instructions for passing on hereditary
characteristics, such height, hair or eye colour. They can also contain instructions
that make you susceptible to certain diseases such as Type 1 diabetes or sickle-cell
anaemia.
It was realised that altering people’s genes could have many medical
applications. Faulty genes could be repaired or inactivated and new genes
could be introduced to help fight specific diseases. The new genes could be
introduced into the body where they would gradually take over from the defective
ones. Eventually the patient would move to improved health. This approach
is known today as gene therapy.
Although still in its infancy, this technology has been used with some success.
But interfering with DNA is a complicated process. Introducing new genetic
material can cause unforseen complications and even development of other illnesses.
Switching the disease off
Antisense therapy is a type of gene therapy being developed to treat HIV infection,
lung cancer, diabetes, asthma and arthritis and even erectile dysfunction.
When a particular gene is known to cause a particular disease, it is possible
to make a strand of DNA that will bind to and inactivate that gene, effectively
switching it ‘off’. The manufactured DNA is called antisense because
its structure is complementary but opposite to the gene’s structure.
Researchers want to develop gene therapy to correct genetic abnormalities
in hitherto untreatable diseases. Recently, a very small clinical trial demonstrated
that it may be possible to treat HIV infection using a genetically modified
version of the HIV virus itself.
How HIV hijacks our cells
During HIV infection, the virus slowly dismantles our immune systems. The
virus attaches itself to the surface of our key immune cells, the CD4 cells,
and injects its own genes inside.
These injected genes start to take over the cell. The CD4 cell’s own
genes are switched off and it is re-programmed to produce new HIV. The CD4
cell is no longer able to replicate itself and defend the person against invading
micro-organisms. This is why the number of our CD4 cells starts to fall as
HIV progresses, and that is why we start to become ill.
New horizons
A new line of treatment for HIV at an early stage of development involves
removing some healthy CD4 cells from people living with HIV. A modified HIV
virus that is unable to replicate is then introduced into the cells and they
are returned to the patient’s body. The modified virus then injects
a gene into the CD4 cells, sabotaging the process by which HIV reproduces
itself. This blocks HIV’s ability to replicate.
So far the technique has been studied over nine months in just five treatment-experienced
men who had previously used an average of seven HIV drugs. At the start all
had a viral load above 20,000 copies and their CD4 counts ranged from 220
to 316. CD4 counts stayed steady or rose in four participants while HIV viral
load remained steady or decreased in all five men.
Importantly, up to 36 months after starting treatment, there was no sign of
dangerous mutations or side effects caused by inserting the gene. It is these
complications that have scuppered other gene therapy clinical trials. And
the researchers found no evidence that the genetically modified HIV was replicating.
Research team leader Carl June, at the University of Pennsylvania School of
Medicine, said the results were “encouraging” and demonstrated
that gene therapy “has the potential to treat HIV and other serious
human diseases”.
The modified HIV virus they used, VRX496, is manufactured by the VIRxSYS Corporation
of Gaithersburg, in the US, who part-funded the study along with the US National
Institutes of Health.
This is only the beginning of a long road. The five patients in the study
will have to be followed up annually for the next 15 years and larger and
longer trials are needed before it is possible to establish if the modified
virus will be useful in controlling HIV in the long-term.
Other
research
A second gene therapy clinical trial involving HIV is also underway. Participants
have virus that is currently well controlled by existing antiretroviral drugs.
Participants can opt to interrupt their therapy to see if the gene therapy
is capable of controlling HIV. The first results should be available in 2007.
If successful, gene therapy would have the advantage of being a one-off therapy,
with the modified genes spreading to other cells in the body. But because
of the complex chemical process necessary to make the modified antisense gene,
this treatment is tailored to individuals and is likely to be expensive.
Dr Martin Haas, of the University of California, San Diego, told the Washington
Post: “This [work] should make quite some noise. I think they have really
significant prospects to develop this into serious anti-HIV approaches for
those patients in whom HIV cannot be kept under control by chemical means.”
Blocking entry
A different strategy of gene therapy in combating HIV is being developed at
the Universities of Frankfurt and Hamburg in Germany. There, scientists are
developing a way of using gene therapy to block HIV’s entry into healthy
CD4 cells.
The method is similar to the mechanism used by the HIV fusion inhibitor, T-20
(Fuzeon). T-20 prevents HIV binding to the surface of the healthy CD4 cell,
preventing it from getting inside and damaging it in the first place. People
taking T-20 must give themselves a small subcutaneous (just under the skin)
injection twice a day.
The gene therapy approach involves infecting healthy CD4 cells with a virus
carring a modified gene. The healthy cell will then cause the CD4 cell to
synthesise the fusion inhibitor molecule itself.
This way, the potent pharmaceutical chemical that blocks fusion of the unwanted
virus with the healthy cell is always present in the cell and in future generations
of that cell. The first volunteer was treated by injection in January 2004.
So far, no safety or efficacy data have been presented.
A rollercoaster journey
There are several other ongoing studies using gene therapy to treat HIV. But
over the past decade research using gene therapy to treat illness in general
has been a rollercoaster of enthusiasm and disappointment. Gene therapy still
faces many challenges, not the least the need for funding and the scientists’
struggles to turn novel ideas into useful therapy for people.
Gene therapy won’t offer a quick cure for HIV and is unlikely to replace
the hugely successful treatments we currently have any time soon. But it is
becoming an increasingly important part in the future of HIV treatment, offering
a new frontier for a cure, and great promise for new treatments.
