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09 November 2008
Under strict embargo until 18.00 (London) 9 November 2008
HIV is a master of disguise, able to rapidly change its identity and hide undetected in infected cells. But now, Cardiff University scientists have helped engineer immune cells to act as "bionic assassins" which 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 them.
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.
Now, 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 which can 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.
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 assassin cells, the virus will either die or be forced to change its disguises again, weakening itself along the way," said 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 in the journal Nature Medicine.
1. Varela-Rohena, A. et al. Control of HIV-1 immune escape by CD8 T-cells expressing enhanced T-cell receptor. Nature Medicine, published online 9 November 2008.
2. Since the discovery of the human immunodeficiency virus (HIV) in 1984 and its role in the cause acquired immunodeficiency syndrome (AIDS) the HIV pandemic has become one of the most serious challenges to human health in the 21st Century. UNAIDS estimates indicate that over 33 million people are now living with HIV rising by approximately 1 million per year. Whilst combinations of highly active anti-retroviral therapy have been relatively successful in crippling the virus and delaying by years the onset of AIDS, crucially such therapy does not represent a cure and the combined problems of drug resistance mutations, toxicity and patient adherence raise questions about the long-term efficacy of treatment as well as the cost and availability of such drugs in poorer parts of the world where the pandemic is most acute. More recently, hopes that vaccines could be used to control the disease by provoking an immune response to the virus have also begun to fade as it has become apparent that HIV’s phenomenal capacity for variation enables it to out-run, and eventually over-run, the human immune system . New approaches are needed that reach beyond these existing efforts, barrier methods and behavioural changes which can truly prevent or cure HIV infection.
3. Cardiff School of Medicine
Cardiff University’s School of Medicine is a significant contributor to healthcare in Wales, a major provider of professional staff for the National Health Service and an international centre of excellence for research delivering substantial health benefits locally and internationally. The school’s 800 staff include 500 research and academic staff who teach more than 2,000 students, including 1,110 postgraduate students.
The School is based at the Heath Park Campus, a site it shares the University Hospital of Wales, the third largest university hospital in the UK. The School has an all-Wales role, contributing greatly to promoting, enhancing and protecting the nation’s health. A key partner in this role is the National Health Service (NHS) in Wales, with which the School is linked at all levels. This mutual dependency is illustrated by the teaching of medical undergraduates in more than 150 hospitals located in all of Wales’ health authorities. The medical curriculum followed at the School enables students to acquire and apply knowledge, skills, judgement and attitudes appropriate to delivering a high standard of professional care. Around 300 new doctors currently graduate from the School every year and the Welsh Assembly Government has invested substantially in new teaching facilities to increase this number further.
The School is an international leader in basic and clinically applied research activities and scored highly in the most recent Government Research Assessment Exercise. School of Medicine researchers annually win tens of millions of pounds in research awards to work with Government, the healthcare industries and the charitable sector on the most pressing issues of human health. The School has six interdisciplinary research groups to draw upon its own strength in depth and the vast range of expertise available across Cardiff University. These groups are addressing cancer; health sciences research; cardiovascular sciences; genomic approaches to health and disease; infection, immunity and inflammation; metabolism repair and regeneration. The School continually invests in facilities, with major developments including the Henry Wellcome Building for Biomedical Research in Wales, the largest enterprise of its kind ever in Wales. This £11M centre contains research laboratories and facilities for patients to participate in investigations of new disease treatments.
The School has been instrumental in establishing and running many important national research initiatives including the Wales Gene Park, Wales Cancer Bank, the Cardiff Institute for Tissue Engineering and Repair and the Healing Foundation UK Centre for Burns Research. The Wales Gene Park is involved in biomedical research, the provision to the NHS of novel diagnostic and clinical services, knowledge dissemination, genetics and genetics education, and the successful commercialisation of innovations arising from such activities. The Wales Cancer Bank is a collaborative project involving several Welsh NHS Trusts, the universities of Bangor and Swansea and the Welsh Assembly Government and is the first population-based collection of tumour and control tissue samples in Wales. The research will help establish the causes of cancer, help identify new areas for treatment and find out the best way to care for individual patients. The Cardiff Institute for Tissue Engineering and Repair uses scientific research to solve problems which are placing a heavy burden on health services around the world, such as, eye repair, chronic wounds, kidney repair and sports injuries. The Healing Foundation UK Centre for Burns Research is a multi-million pound collaboration investigating treatments and support fort the physical and mental rehabilitation of the 14,000 people suffering severe burns in the country every year.
4. The Wellcome Trust is the largest charity in the UK. It funds innovative biomedical research, in the UK and internationally, spending over £600 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing.
5. Adaptimmune Limited is focused on the use of T cell therapy to treat HIV and cancer. It aims to utilise the body’s own machinery - the T lymphocyte cell - to target and destroy cancerous or infected cells. Adaptimmune’s mission is to take so-called "adoptive T cell therapy" to the next level by leveraging its expertise in engineering high affinity T cell receptor proteins (TCRs) which recognise the cancerous or infected cells as a means of "supercharging" the strength of patient’s own T cell responses. Established in July 2008 as a separate spin-out company, Adaptimmune was set up to develop Immunocore Ltd’s (formely Avidex/MediGene Ltd’s) unique T cell receptor engineering technology for adoptive T cell therapy, technology originally developed by Avidex when it was spun out from Oxford University. Adaptimmune holds an exclusive licence to the adoptive therapy use of the technology and is aiming to exploit this unique capability in the development of targeted T cell therapy in HIV and cancer through partnership and collaboration with leading institutions in both fields. http://www.adaptimmune.com
6. University of Pennsylvania PENN Medicine is a $3.6 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.
Penn's School of Medicine is currently ranked #4 in the nation in U.S.News & World Report's survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,700 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System (UPHS) includes its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation's top ten "Honor Roll" hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center. In addition UPHS includes a primary-care provider network; a faculty practice plan; home care, hospice, and nursing home; three multispecialty satellite facilities; as well as the Penn Medicine at Rittenhouse campus, which offers comprehensive inpatient rehabilitation facilities and outpatient services in multiple specialties.
7. Oxford University's Medical Sciences Division is one of the largest biomedical research centres in Europe. It represents almost one-third of Oxford University's income and expenditure, and two-thirds of its external research income. Oxford's world-renowned global health programme is a leader in the fight against infectious diseases (such as malaria, HIV/AIDS, tuberculosis and avian flu) and other prevalent diseases (such as cancer, stroke, heart disease and diabetes). Key to its success is a long-standing network of dedicated Wellcome Trust-funded research units in Asia (Thailand, Laos and Vietnam) and Kenya, and work at the MRC Unit in The Gambia. Long-term studies of patients around the world are supported by basic science at Oxford and have led to many exciting developments, including potential vaccines for TB, malaria and HIV, which are in clinical trials. http://www.ox.ac.uk
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