Natural Killer (NK) cell regulation of antiviral T cell responses in the pathogenesis of HIV infection

Around 40 million people are currently living with HIV around the globe. HIV remains a leading infectious killer in the world having claimed in excess of 36 million lives to date. Infection with HIV targets the immune system and leads to progressive deterioration of people's ability to survey for and fend off infections and some types of cancer. As the virus impairs and destroys the function of immune cells, affected individuals become gradually more immunocompromised. The most advanced stage of HIV infection is AIDS. Although there is no cure for HIV to date, combination therapy with anti-HIV agents called antiretroviral therapy (ART), prevents the virus from multiplying in the body but cannot eradicate it, stalling the destruction of the body's immune cells.
Although effective treatment has resulted in obvious health benefits, accumulating toxicity as a result of lifelong therapy and universal access to therapy are remaining concerns. In addition, ongoing activation of the immune system as seen in treated individuals accounts for a significant proportion of non-AIDS health problems and associated deaths. There is therefore a widely acknowledged need for the development of new and innovative treatments to improve current therapies.

The main immune cell type fighting the virus, the T cell, is severely impaired and debilitated during chronic infection. In this study we will be investigating the ability of another type of cell called Natural Killer (NK) cell, to kill the beneficial T cells limiting their antiviral potential. Malfunctioning NK cells may also attack healthy T cells, causing chronic disease instead of fighting it.

The purpose of this study is to identify the possible NK cell-mediated pathways leading to T cell deletion. We will use blood samples obtained during routine clinical care of patients infected with HIV following informed consent. Blocking these harmful pathways will boost the immune system leading to improved viral control and prevention of chronic disease and complications.

Aims objectives:
Accumulating evidence indicates the involvement of NK cells in the control of viral infections and shaping of adaptive immunity. Our recent work was the first to identify a novel pathway for direct NK cell regulation of T cells in chronic HBV infection in humans. These emerging data challenge the paradigm of NK cell function during viral infections and may be particularly relevant in HIV infection. We aim to investigate the ability of NK cells to limit the antiviral response in HIV infection and the role of immune activation in driving NK cell mediated T cell lysis. We will also explore the role of Killer Immunoglobulin Receptor (KIR) diversity in controlling NK cell regulation of T cells in HIV, providing a mechanistic model for the striking genetic KIR/HLA associations influencing HIV outcome.

Design and methodology:
We will utilise PBMC from four diverse and well-characterised cohorts of HIV infected individuals (early, established HIV with different levels of viraemia, well controlled on cART, and elite controllers) to help us evaluate the mechanisms and triggers that could regulate this process during dynamic disease phases. Functional experiments with blocking antibodies and NK cell depletion will allow us to determine the capacity of NK cells to kill autologous virus-specific T cells from patients with different disease profiles, and to investigate whether HIV-specific T cells are more susceptible than T cells of other specificities in the same patients. Subgroup immunogenetic analyses will help determine any independent effects, especially of HLA-C allotypes, ligands for the inhibitory 2 domain KIRs.

Scientific and medical opportunities:
Uncovering the precise mechanisms in place that regulate NK cell mediated immune suppression of T cells during HIV infection will facilitate the development of novel therapeutic strategies that can supplement ongoing efforts to restore antiviral immunity and reduce disease burden.

Academic/Clinical
A main strength of this proposal is that it spans a range of disciplines including virology, immunology, genetics and infectious diseases. It would therefore be beneficial to researchers/clinicians working in these areas. With the global disease burden of HIV the potential impact/benefit of this work will be both national and international. With dissemination of our results, researchers around the world would benefit from the methodologies and data generated. Interactions at conferences and meetings will also encourage existing and new collaborations paving the way for new research projects. The potential of new highly innovative treatment strategies would allow clinicians to advise patients regarding availability of newer treatment options.

Pharmaceutical, Business & Industrial
Identifying potential targets for immunotherapy would foster collaborations with industrial partners. By designing adjuvant agents for chronic HIV infection, this would lead to further drug trials and drug licensing, benefiting a multitude of people including those actively involved with clinical trials.

Other Support
A further consequence is the possibility for creation of new jobs within the pharmaceutical industry and industrial sector. The creation and growth of companies and jobs will increase business revenue and economic prosperity.

Health service
Another important beneficiary of this work would be the NHS management service. By increasing our understanding of HIV immunopathogenesis we may be able to identify markers of disease progression/response to treatment in addition to molecular targets for immunotherapy. We may therefore be able to define who is more likely to have a favourable prognosis and tailor treatment to the individual. Moreover, the potential for development of new adjuvant treatments would encourage the creation of new research jobs, nursing posts for drug trials and administrative positions, benefiting employment and the UK economy.

Legal/Economic sector
Patenting and development of new therapeutic strategies would require input from the legal and economic sector supporting drug regulatory bodies for approvals. They would also participate in regional and local decisions regarding drug funding and licensing.

Scientists/Statistician/IT
Basic scientists and technicians involved in this project will benefit from expanding their technical skills and research portfolio enhancing their job opportunities. In addition to basic research skills this project will offer numerous opportunities for developing their transferable and presentation skills. Generation of data for dissemination and publication will also require statisticians and IT staff in order to compile and analyse data, augmenting the research team infrastructure.

General Public
The general public plays an essential role in research, affecting decisions. It is therefore important that we contribute to public awareness and foster public engagement via a variety of means (see public engagement in science). This is particularly important for any relevant advances that may be transferable to the patient setting.

Schools
This work will also benefit the next generation scientists/clinicians. Through an extensive educational outreach programme we seek to involve children increasing their knowledge of medical research. Via our close links with the university and basic science/medical programmes we will inform undergraduates and involve BSc students with ongoing research.

Government
One of the main priorities of Public Health England is to reduce the burden of HIV by improving co-ordination, effectiveness and impact of HIV services in support of the new National Sexual Health Framework for England. This proposal aims to better characterise the factors contributing to the failure of the immune response to clear HIV with a view to restore them ultimately reducing disease burden; an important government target.