Download retroviruses: keeping the enemy closer

nurture infectious diseases
JULY 2012
RETROVIRUSES: KEEPING
THE ENEMY CLOSER
Scientists have discovered ways in which
these notorious infectious agents could
revolutionise medical treatments
Liam A. Hurst
VERYONE knows retroviruses are
killers. They can cause leukaemia,
damage neurons and they terrorise our
immune system. The much feared human
immunodeficiency virus (HIV), a retrovirus
responsible for acquired immunodeficiency
syndrome (AIDS), is one of the most
debilitating and ultimately fatal infectious
diseases known to man. Death from AIDSassociated infection is ranked alongside
cardiovascular disease, cancer and diabetes
as one of the biggest causes of mortality
worldwide. So naturally, we only think of
retroviruses as enemies.
E
TERRORIST BEHAVIOUR
Who can blame us? Retroviruses act
like terrorists. They infiltrate our
unsuspecting cells and then disguise
themselves, transforming their genetic code
from RNA to DNA, with the help of their
reverse transcriptase enzyme. This deception
allows them to integrate into our own
cellular DNA, where they hide, avoiding
detection by our immune system. Our
hijacked cells are then forced to create
multiple copies of the retrovirus which break
out to infect other innocent cells in our body.
Whilst this sneaky behaviour makes
combating retroviral infection extremely
problematic, it is these very same survival
techniques that give the retrovirus great
potential in biomedical research.
COULD HIV BECOME YOUR NEW BEST FRIEND?
DNA DELIVERY BOY
So how can something so dangerous be
of any benefit to us? The answer lies in genetic
modification. The retrovirus can be stripped of
its disease-causing genes and rebuilt with
desired genetic material, whilst retaining its
innate ability to integrate its genome into our
cells. The retrovirus is thus transformed from a
potent infectious agent to a non-virulent DNA
delivery vehicle, capable of transporting and
integrating useful genes into cells.
Regenerative medicine and gene therapy are
just two examples where being ‘infected’ with
this type of retrovirus could actually save your
life.
The essence of regenerative medicine
lies in using pluripotent stem cells, selfrenewing cells capable of becoming any cell
type of our choosing. Originally, stem cells for
research were derived from human embryos
but, in addition to well-known ethical
concerns, there remained the constant worry of
tissue rejection. However, retroviruses now
offer a tantalising alternative. In 2007, Shinya
Yamanaka at Kyoto University, Japan,
discovered a way of manufacturing
personalised stem cells from an individual’s
mature cells1.
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“Being
infected
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could be cause for celebration”
He recognised that, if four genetic markers of
pluripotency - normally disabled after
embryonic development - were reactivated,
they would reset the developmental clock,
returning any cell to its pluripotent state. Using
a genetically modified retrovirus to re-insert
the four markers, he was able to create induced
pluripotent stem cells which carry unique
genetic identifiers. These identifiers would
allow personal tissues to be grown and
transplanted without fear of rejection, as well
as opening up medicine to the possibility of
bespoke clinical treatments.
But the uses of the retrovirus don’t end
there. Gene therapy utilises DNA as a catalyst
in eliminating disease, by overriding mutated,
non-functioning genes with working copies.
With help from retroviruses, gene therapy
trials are showing promise in treating several
hereditary diseases. X-linked chronic
granulomatous disease is one such example, a
condition
in which,
because
of a defective
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gene called glycoprotein 91 (GP91), patients
are unable to efficiently destroy pathogens that
invade the body, making them susceptible to
recurrent severe infections. In 2010, scientists
at the National Institutes of Health, Bethesda,
USA, introduced functional GP91 into white
blood cells of two adult patients, using a
retrovirus as a transport device, and found that
over an eleven-month period their ability to
eradicate infection improved significantly2.
The successes of regenerative medicine
and gene therapy trials are largely attributable
to the retrovirus’s broad infectivity range and
long-term activation of the introduced genetic
elements. These traits, fundamental to
retroviral pathogenesis, are what has made
them one of the current mainstays for delivery
of exogenous genetic material.
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But this biological instrument, whilst
impressive, is not without its limitations.
Retroviruses by their very nature are
unpredictable; they randomly insert
themselves into genomes, and consequently
might activate genes that would otherwise be
left dormant. The development of tumours
due to sustained activation of genes that
control cell division has scuppered several
gene therapy trials. This unpredictability is
also evident in the haphazard workings of the
retrovirus’s reverse transcriptase enzyme. It
can, while converting retrovirus RNA to DNA,
introduce mutations which inactivate the
inserted gene, requiring repeated delivery
attempts and, consequently, repeated viral
exposure. A final, more pressing concern is
whether we should be using a retrovirus,
something normally so harmful, to improve
human health. The fact remains that it is a
virus. OK, that pathogenicity has been
attenuated but, once in a patient, who knows
what could rear its ugly head?
Whilst we are far from being ‘BFFs’
with retroviruses it’s safe to say we no longer
need to view them with such consternation.
Like any tool, if used appropriately the
retrovirus may prove to be invaluable. Who
knows? Once retroviral gene-delivery systems
have been perfected, being ‘infected’ with a
retrovirus could be cause for celebration.
REFERENCES
1. Takahashi, K. et al. (2007) Cell 131;5:
861–872
2. Kang, E.M. et al. (2010) Blood 115;4: 783791
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