Nov 10 2008
HIV is a master of disguise, able to rapidly change its identity and hide undetected in infected cells. But now, in a long-standing collaborative research effort partially-funded by the Wellcome Trust, scientists from Oxford-based Adaptimmune Limited, in partnership with the Universities of Cardiff and Pennsylvania have engineered immune cells to act as "bionic assassins" that see through HIV's many disguises.
The findings of the study, published online today in the journal Nature Medicine, may have important implications for developing new treatments for HIV and slowing – or even preventing – the onset of AIDS. 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.
When viruses enter our bodies, they hijack the machinery of host cells in order to replicate and spread infection. When our body's cells are infected with a virus they expose small parts of the virus on their surface, offering a "molecular fingerprint" called an epitope for killer T-cells from the immune system to identify. This triggers an immune response, eliminating the virus and any cells involved in its production.
As with other viruses, HIV enters the body and replicates itself rapidly. However, it also has the ability to mutate quickly, swiftly disguising its fingerprints to allow it to hide from killer T-cells.
"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," explains Professor Andy Sewell from Cardiff University, co-lead author of the study and long-term collaborator with Adaptimmune. "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."
Now, Professor Sewell and colleagues from Adaptimmune Ltd and the University of Pennsylvania School of Medicine 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 "bionic assassins" able to destroy HIV-infected cells in culture.
"The T-cell receptor is nature's way of scanning and removing infected cells – it is uniquely designed for the job but probably fails in HIV because of the tremendous capability of the virus to mutate," says Dr Bent Jakobsen, co-lead author and Chief Scientific Officer at Adaptimmune Ltd, the company which owns the technology. "Now 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 assassin 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, Professor Carl June and Dr James Riley from the University of Pennsylvania in Philadelphia will shortly begin clinical trials using the engineered killer T-cells.
"We hope to begin testing the treatment on patients with advanced HIV infection next year," says Professor June. "If the therapy in that group proves successful, we will treat patients with early stage well-controlled HIV infection. The goal of these studies is to establish whether the engineered killer T cells are safe, and to identify a range of doses of the cells that can be safely administered."
"The AIDS virus evades human immunity in all it infects," says Professor Rodney Phillips, from the University of Oxford, where the collaborative research effort first began in 2003. "Until now no-one has been able to clear the virus naturally. Immune cells modified in the laboratory in this way provide a test as to whether we can enhance the natural response in a useful and safe way to clear infected cells. If successful the technology could be applied to other infectious agents."
The researchers are now exploring using engineered receptors on killer T-cells as a way of improving immune responses to cancer.