The winning entry in the Cambridge Infectious Diseases Science Writing Competition
Scientists have discovered ways in which these notorious infectious agents could revolutionise medical treatments
Liam A. Hurst
Everyone 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 AIDS associated 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.
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 .
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, self renewing 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.
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 will 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 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 high infectivity rate 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.
CAUSE FOR CONCERN
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: 783- 791
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HIV 3D image reproduced by kind permission of Visual Science.