Natural Killer (NK) cell regulation of antiviral T cell responses in the pathogenesis of HIV infection
Lead Research Organisation:
University of Oxford
Department Name: Target Discovery Institute
Abstract
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.
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.
Technical Summary
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.
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.
Planned Impact
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.
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.
People |
ORCID iD |
Dimitra Peppa (Principal Investigator / Fellow) |
Publications
Alrubayyi A
(2021)
Characterization of humoral and SARS-CoV-2 specific T cell responses in people living with HIV.
in bioRxiv : the preprint server for biology
Alrubayyi A
(2020)
Harnessing Natural Killer Cell Innate and Adaptive Traits in HIV Infection.
in Frontiers in cellular and infection microbiology
Alrubayyi A
(2022)
Natural killer cells during acute HIV-1 infection: clues for HIV-1 prevention and therapy
in AIDS
Alrubayyi A
(2021)
Characterization of humoral and SARS-CoV-2 specific T cell responses in people living with HIV.
in Nature communications
Alrubayyi A
(2022)
Functional Restoration of Exhausted CD8 T Cells in Chronic HIV-1 Infection by Targeting Mitochondrial Dysfunction.
in Frontiers in immunology
Alrubayyi A
(2021)
Seeing SARS-CoV-2 variants through the eyes of T cells.
in Nature reviews. Immunology
Cubero EM
(2020)
Subordinate Effect of -21M HLA-B Dimorphism on NK Cell Repertoire Diversity and Function in HIV-1 Infected Individuals of African Origin.
in Frontiers in immunology
Dickinson M
(2020)
Dynamics of Transforming Growth Factor (TGF)-ß Superfamily Cytokine Induction During HIV-1 Infection Are Distinct From Other Innate Cytokines.
in Frontiers in immunology
Gupta RK
(2019)
HIV-1 remission following CCR5?32/?32 haematopoietic stem-cell transplantation.
in Nature
Gupta RK
(2020)
Evidence for HIV-1 cure after CCR5?32/?32 allogeneic haemopoietic stem-cell transplantation 30 months post analytical treatment interruption: a case report.
in The Lancet HIV 2020 (in press)
Huang WC
(2017)
T Cells Infiltrating Diseased Liver Express Ligands for the NKG2D Stress Surveillance System.
in Journal of immunology (Baltimore, Md. : 1950)
Maini MK
(2020)
Shared immunotherapeutic approaches in HIV and hepatitis B virus: combine and conquer.
in Current opinion in HIV and AIDS
Moreno-Cubero E
(2024)
IL-15 reprogramming compensates for NK cell mitochondrial dysfunction in HIV-1 infection.
in JCI insight
Peppa D
(2019)
Entering a new era of harnessing natural killer cell responses in HIV infection
in EBioMedicine
Peppa D
(2017)
Natural Killer Cells in Human Immunodeficiency Virus-1 Infection: Spotlight on the Impact of Human Cytomegalovirus.
in Frontiers in immunology
Peppa D
(2018)
Adaptive Reconfiguration of Natural Killer Cells in HIV-1 Infection.
in Frontiers in immunology
Peppa D
(2021)
Poor Responses to Pneumococcal Vaccination in CKD Patients-Do We Need to Talk About Cytomegalovirus Again?
in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
Scourfield DO
(2021)
The role and uses of antibodies in COVID-19 infections: a living review.
in Oxford open immunology
Singh HD
(2017)
TRAIL regulatory receptors constrain human hepatic stellate cell apoptosis.
in Scientific reports
Touizer E
(2021)
Failure to seroconvert after two doses of BNT162b2 SARS-CoV-2 vaccine in a patient with uncontrolled HIV
in The Lancet HIV
Description | INIMG012 HIV frontiers from research to clinic |
Geographic Reach | Local/Municipal/Regional |
Policy Influence Type | Influenced training of practitioners or researchers |
Description | Determining the immunological basis for weakened SARS-CoV-2 vaccination outcomes |
Amount | £425,104 (GBP) |
Funding ID | MR/W020556/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 08/2021 |
End | 08/2022 |
Description | Effect of HLA-B dimorphism on NK cell mediated immunity during chronic viral infections |
Amount | £20,000 (GBP) |
Funding ID | ID: 3711160 |
Organisation | Association of Physicians of Great Britain and Ireland |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 10/2018 |
End | 09/2019 |
Description | Evolution of NK cell responses during acute HIV infection with distinct viral subtypes |
Amount | £15,000 (GBP) |
Organisation | British HIV Association (BHIVA) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 12/2019 |
End | 12/2020 |
Description | Exploiting Natural Killer cells in HIV/HBV co-infection to achieve eradication R01AI155182 National Institute Of Allergy And Infectious Diseases |
Amount | $1,980,000 (USD) |
Funding ID | R01AI155182 |
Organisation | National Institute of Allergy and Infectious Diseases (NIAID) |
Sector | Public |
Country | United States |
Start | 07/2020 |
End | 06/2025 |
Title | New patient database |
Description | Generated new research database including patient samples following successful ethical approval. |
Type Of Material | Database/Collection of data |
Year Produced | 2018 |
Provided To Others? | No |
Impact | Building a new cohort of HIV infected patients and stored samples for current and future work. Replenishing research samples has been essential for my current work and has strengthened collaborations. We have now generated a new cohort of HIV infected individuals followed up longitudinally pre and post therapy. |
Description | Collaboration with Dr Gupta at UCL |
Organisation | University College London |
Department | Division of Infection and Immunity |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | My project address an important and novel area of HIV immunology, investigating NK cell mediated regulation of T cell responses. This work will complement ongoing research at UCL in particular in elite controllers. |
Collaborator Contribution | Provide access to patients and samples recruited to our elite controller study as well as other patients on ART. Access to KIR and HLA data on our cohort, as well as PBMC. |
Impact | Ongoing work. 10.1038/s41586-019-1027-4 |
Start Year | 2015 |
Description | Oxford collaboration |
Organisation | University of Oxford |
Department | Nuffield Department of Medicine |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | My proposed studies complement other work ongoing in Dr Borrow's group, including projects addressing HIV-specific CD8 T cell responses and their evasion by viral mutational escape by exhaustion during acute and early HIV-1 infection. |
Collaborator Contribution | I have been collaborating closely with Dr Borrow in Oxford. Dr Borrow leads a research group in the Nuffield Department of Medicine at Oxford University, much of the work currently being conducted by which focuses on analysis of innate and T cell responses in human immunodeficiency virus type 1 (HIV-1) infection. Our goals are to identify immunological mechanisms contributing to protection and pathogenesis during acute and early HIV-1 infection, to inform the rational development of effective immune-based prophylactic and therapeutic strategies to combat this infection. Subsequent to a year secondment from UCL to Oxford I have now formally transferred my fellowship to Oxford University with effect from the 1 December 2017. I have built strong links with not only Dr Borrow's group but the other HIV groups in the Unit including Prof Sarah Rowland-Jones. Prof Dorrel, Dr Gillespie and Sir Prof Andrew McMichael. |
Impact | Given the early stage of collaborating I have concentrated on acquiring the necessary skill sets that are fundamental for the success of the project. We have been sharing reagents and patient samples successfully and optimised assays and experimental protocols fruitfully. 10.3389/fimmu.2018.00474 |
Start Year | 2015 |
Description | PROACTIV study |
Organisation | Merck |
Department | Merck Sharp and Dohme Ltd |
Country | United Kingdom |
Sector | Private |
PI Contribution | Investigator Studies Programme - I have been leading on the immunology component of the study (currently undergoing ethical approval) to examine the role of a novel anti-CMV drug in HIV infected patients. This is going to be an open label randomised trial taking place at the RFH. I have contributed my expertise and intellectual input in the design of the trial and will be responsible for the immunological studies (primary endpoints) that will be performed in Oxford. |
Collaborator Contribution | MSD is providing access to the drug and financing component of the study which will take place at the RFH with Prof Margaret Johnson and her research clinical trials team. |
Impact | We are anticipating ethical approval and contracts' agreement in he next couple of months and recruitment to commence within the next 6 months. |
Start Year | 2019 |
Description | PROACTIV study |
Organisation | Royal Free Hospital |
Country | United Kingdom |
Sector | Hospitals |
PI Contribution | Investigator Studies Programme - I have been leading on the immunology component of the study (currently undergoing ethical approval) to examine the role of a novel anti-CMV drug in HIV infected patients. This is going to be an open label randomised trial taking place at the RFH. I have contributed my expertise and intellectual input in the design of the trial and will be responsible for the immunological studies (primary endpoints) that will be performed in Oxford. |
Collaborator Contribution | MSD is providing access to the drug and financing component of the study which will take place at the RFH with Prof Margaret Johnson and her research clinical trials team. |
Impact | We are anticipating ethical approval and contracts' agreement in he next couple of months and recruitment to commence within the next 6 months. |
Start Year | 2019 |
Description | PancrImmune Collaborative (Oxford) |
Organisation | University of Oxford |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Nk cell expertise and contribution to the design and analysis of single cell data derived from cancer specimens to determine the contribution of NK cells in a variety of GI cancers. |
Collaborator Contribution | My collaborators have provided access to data and samples for analysis. |
Impact | The analysis is still ongoing and we anticipate research outputs to arise in the coming year. |
Start Year | 2019 |
Description | Clinical Research teams |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Professional Practitioners |
Results and Impact | Workshop with the clinical trials team and allied health professional to highlight the benefits of translational research (from clinic to bench and back to the clinic). This meeting sparked a number of questions and useful discussions in better bridging the interface between clinical and research work. |
Year(s) Of Engagement Activity | 2017 |
Description | Patient group workshops |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Study participants or study members |
Results and Impact | 50 research participants (Jenner II study; observational cohort study that I am currently running at MMC) attended this workshop. The main aim was to present research findings directly derived from research specimens obtained from our participants. This was an ideal opportunity to involve our participants in our current study and generate questions that will help inform our future work with direct clinical impact in their future management. |
Year(s) Of Engagement Activity | 2019,2020 |