Engineered Killer T Cell Recognizes HIV-1's Lethal Molecular Disguises

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.

Background on HIV

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.