Engineered killer T cell recognizes HIV-1's lethal molecular disguises

PHILADELPHIA – Researchers at the University of Pennsylvania School of Medicine and colleagues in the United Kingdom have engineered T cells able to recognize HIV-1 strains that have evaded the immune system. The findings of the study, published online in the journal Nature Medicine, have important implications for developing new treatments for HIV, especially for patients with chronic infection who fail to respond to antiretroviral regimens.

When viruses enter the body, they hijack the machinery of host cells to replicate and spread infection. When the 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 see. This triggers an immune response, eliminating the virus and any cells involved in its production. However, HIV has the ability to mutate quickly, swiftly disguising its fingerprints to allow it to hide from killer T-cells.

Natural T cells recognize their targets through weak molecular interactions mediated by the T cell receptor. Through a clever molecular process, the investigators were able to isolate a group of T cell receptor encoding genes that bind to HIV-1 about 450-fold more strongly.

"Not only could T cells engineered to express the strongly binding T cell receptor see HIV strains that had escaped detection by natural T cells, but the engineered T cells responded in a much more vigorous fashion so that far fewer T cells were required to control infection," says co-senior author James Riley, PhD, Research Associate Professor of Pathology and Laboratory Medicine at Penn.

What's more, adds first author Angel Varela-Rohena, PhD, who recently completed these studies as part of his PhD dissertation, "With the present availability of potent systems to replicate and deliver high-affinity HIV-1 specific T-cell receptors, billions of these anti-HIV-1 warriors can be generated in two weeks."

"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," explains Professor Andy Sewell from Cardiff University, United Kingdom, co-senior author of the study. "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. We'd prefer the first option but I suspect we'll see the latter."

"We hope to begin clinical trials using the engineered T cells in patients with advanced HIV infection next year, a group for whom many drug regimens have stopped working" says co-author Carl June, MD, Professor of Pathology and Laboratory Medicine and Director of Translational Research at the Abramson Family Cancer Research Institute at Penn. "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."

"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," says Bent Jakobsen, PhD, co-lead author and Chief Scientific Officer at Adaptimmune Ltd, the United Kingdom-based company which owns the rights to the technology. "If we can translate those results in the clinic, we could at last have a very powerful therapy on our hands."

This study was funded in part by the National Institute of Allergy and Immune Diseases and Wellcome Trust, UK.

The Penn authors have no financial interest or other relationship with Adaptimmune LTD, apart from their scientific collaboration in developing the engineered killer T cell, conducting laboratory experiments and planning human clinical trials.

This release and related images can be viewed at www.pennhealth.com/news.

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.

Additional Media Contacts

Craig Brierley
Media Officer
The Wellcome Trust, UK
T: +44 (0)20 7611 7329
E: c.brierley@wellcome.ac.uk

Victoria Dando
Public Relations Officer
Cardiff University, UK
T: +44 (0)29 2087 9074
E: DandoV2@cardiff.ac.uk

Margaret Henry
PR Consultant
Adaptimmune Ltd, UK
T: +44 (0)1865 811199
E: m.henry@oxin.co.uk

Notes for editors

1. 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.

2. 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. http://www.wellcome.ac.uk

3. Cardiff University The School of Medicine at Cardiff is one of the largest in the UK, employing nearly 500 academic and 300 support staff with over 1,000 undergraduate and 1,100 postgraduate students currently enrolled on medical and science courses. The School has an annual financial turnover of over £50 million, of which nearly 50% comes from competitive external research funding. This will increase in the next one to three years as the recent increase in research funding awards feeds through into annual income. The relationship of the School of Medicine with the National Health Service (NHS) is a positive and dynamic one, driven by the close links of the University with the Welsh Assembly Government. Over 750 staff from the Medical School are on clinical contracts with the NHS, and staff from across all seven NHS Trusts within Wales are similarly involved in teaching activity with the University. http://www.cardiff.ac.uk/medic

4. 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

5. 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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