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HIV's disguises no match for engineered cells

10 November 2008

HIV is a master of disguise, able to rapidly change its identity and hide undetected in infected cells. But now, Cardiff scientists have helped engineer immune cells that see through HIV’s many disguises.

Co-led by Professor Andy Sewell, of the School of Medicine, the research may have important implications for developing new treatments for HIV and slowing - or even preventing - the onset of AIDS.

When viruses enter our bodies, they hijack host cells in order to replicate and spread infection. Small parts of the virus become exposed on the surface of the cell, offering a ‘molecular fingerprint’ for killer T-cells from the immune system to identify, and destroy.

However, HIV has the ability to mutate and disguise its fingerprints, allowing it to hide from killer T-cells. This capacity for disguise or ‘immune escape’ ensures that the human immune system is unable to rid the body of HIV.

Professor Sewell, and colleagues from the University of Pennsylvania’s School of Medicine and Adaptimmune Ltd UK have engineered and tested a killer T-cell receptor that is able to recognise all of the different disguises that HIV is known to have used to evade detection. The researchers attached this receptor to the killer T-cells to create genetically engineered T-cells able to destroy HIV-infected cells in culture.

Professor Sewell said: "When the body mounts a new killer T-cell response to HIV, the virus can alter the molecular fingerprint that these cells are searching for in just a few days. It’s impossible to track and destroy something that can disguise itself so readily. As soon as we saw over a decade ago how quickly the virus can evade the immune system we knew there would never be a conventional vaccine for HIV."

Over 33 million people were estimated to be living with HIV worldwide in 2007. Although anti-retroviral drugs have been successful in delaying the onset of AIDS for several years, the drugs are expensive, have serious side effects and must be taken for life. No vaccine or cure yet exists and drug resistance is increasingly becoming a problem.

Dr Bent Jakobsen, Chief Scientific Officer at Adaptimmune Ltd, said: "We have managed to engineer a receptor that is able to detect HIV’s key fingerprints and is able to clear HIV infection in the laboratory. If we can translate those results in the clinic, we could at last have a very powerful therapy on our hands."

The researchers believe that HIV's chameleon-like ability may still prevent the virus from being completely flushed out of the body. It could mutate and change its fingerprint further, hiding behind these new disguises and evading detection. However, each time the virus is forced to mutate to avoid detection by killer T-cells, it appears to become less powerful.

"In the face of our engineered cells, the virus will either die or be forced to change its disguises again, weakening itself along the way," says Professor Sewell. "We’d prefer the first option but I suspect we’ll see the latter. Even if we do only cripple the virus, this will still be a good outcome as it is likely to become a much slower target and be easier to pick off. Forcing the virus to a weaker state would likely reduce its capacity to transmit within the population and may help slow or even prevent the onset of AIDS in individuals."

Pending regulatory approval, clinical trials using the engineered killer T-cells will begin shortly at the University of Pennsylvania in Philadelphia. The researchers are also exploring using engineered receptors on killer T-cells as a way of improving immune responses to cancer. Initial results indicate that it is possible to engineer human anti-cancer killer T-cells that are substantially better than anything the body is able to produce naturally.

The research was partially funded by the Wellcome Trust and is published online today in the journal Nature Medicine.

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