Natural Killer Cells as Effectors in HIV Cure Strategies

Lead Research Organisation: University of Oxford
Department Name: Experimental Medicine

Abstract

Antiretroviral therapy (ART) has resulted in the life expectancy of HIV infected individuals no longer being significantly less than uninfected people. However, ART must be taken daily, has side effects and comes with significant financial costs. This has placed renewed emphasis on curing HIV. The barrier to a cure is a population of infected cells termed the reservoir, that remain invisible to both therapy and the immune system.

Recent studies have shown that patients treated early in the course of HIV infection have lower viral reservoirs, and some can control viral replication after stopping ART for long periods of time. This is termed 'post treatment control' (PTC), and is a form of remission from HIV infection. If we understand it, PTC may help us find a cure for HIV. As of yet, we cannot predict which patients will and will not become post-treatment controllers. Some data suggests that a type of immune cell - called a Natural Killer (or 'NK') cell - might play an important role in this phenomenon.

In this study, we will use two large cohorts of HIV infected patients who started ART early in infection (called SPARTAC and HEATHER) to determine if characteristics of NK cells can affect reservoir size, how to predict patients who will control viral replication off therapy, and find out how early ART will affect NK cell function. If we can find out how NK cells may help induce control of the virus, such that treatment can be stopped for a while, this will help us plan new treatments as we search for a cure for HIV infection.

Technical Summary

Antiretroviral therapy (ART) successfully controls viral replication but is not a cure for HIV infection. ART requires daily medication (with significant financial costs), has side effects, and patients on ART still face higher risks of various morbidities than uninfected patients. Recent evidence from the VISCONTI cohort suggests a subset of patients treated early in infection can successfully control viraemia for a long period of time following ART cessation. Understanding this phenomenon could help generate therapeutic approaches to reduce the reservoir and guide the design of HIV cure clinical trials where ultimate efficacy will require taking patients off ART. Preliminary data from the VISCONTI cohort suggests that NK cells might play a role in PTC while the role of NK cells on reservoir size in patients on early ART has yet to be studied.

Therefore, we will use samples from two large clinical cohorts of primary infected HIV patients - SPARTAC and HEATHER. The SPARTAC trial randomized patients into one of three arms: no ART (standard of care), 24 weeks of ART, and 48 weeks of ART followed by a scheduled treatment interruption. The HEATHER cohort is the largest cohort of primary infection in the UK with longitudinal samples from patients over time. Additionally, 20 patients in the HEATHER cohort will undergo a scheduled intensively monitored treatment interruption in the PITCH study.

In this application, we will use samples from these 3 studies to examine the phenotype and function of NK cells to determine if NK cells can affect the size of the reservoir, the time to viral rebound in patients who stop ART, and the effect of early ART on NK function.

Planned Impact

The research in the proposal will characterize the relationship between NK cells and reservoir size and post treatment control (PTC)/time to viral rebound post treatment interruption, and analyze the functionality of NK cells in early treated ART patients over time. This work will potentially identify markers of PTC that could identify who might control viraemia for long periods of time after stopping ART.

1. Who will benefit from this research

1.1) Commercial sector i.e. pharmaceutical industry
1.2) Clinical trials units
1.3) Policy makers, e.g. Public Health England
1.4) Healthcare providers, e.g. the NHS
1.5) HIV-infected patients

2. How will they benefit from this research?

2.1) The pharmaceutical industry is interested in a cure for HIV, evidenced by their recent investment (GSK £20,000,000) into a cure center in University of North Carolina, USA. This work would benefit them in two major ways. First, the research might open up a new class of cells to clear a reactivated viral reservoir (NK cells) if they are shown to have a major impact on reservoir size or PTC. Additionally, if NK cell characteristics are shown to impact PTC, industry could use this information when designing their clinical trials especially in terms of a structured treatment interruption where any markers of successful PTC would be of use. A safe treatment interruption would also be the most effective way of evaluating clinical trials for HIV cure.
2.2) Clinical trials units would also benefit from the identification of cell/markers responsible for PTC as this would aid clinical trial design and affect which clinical markers are measured in patients during HIV cure studies.
2.3) Policy makers would be interested in the results of the proposed studies particularly if a subset of patients can be taken safely off ART, which would potentially affect treatment guidelines. Additionally, our results could also guide funding directions in HIV cure studies. This would not be an immediate effect as many clinical studies would be needed to confirm any biomarkers we might find.
2.4) Healthcare providers would be interested in our data as the cost of ART is high (lifetime treatment £361,000) and being able to safely take patients off ART would be cost effective.
2.5) HIV-1 infected patients would benefit from our research for several reasons. Many are interested in cure studies and our research would aid in their design and direction. Additionally, allowing some patients to safely stop ART would free patients from taking medication daily. This is also a long-term benefit as our results would have to be vigorously tested before allowing patients to stop ART.

Publications

10 25 50
 
Description British HIV Association Science and Education Sub-Committee
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
Impact Impact of HIV care guidelines in the UK and national HIV research portfolio
 
Guideline Title British HIV Association Treatment Guidelines 2016 update
Description Citations in British HIV Association Treatment Guidelines 2016 update
Geographic Reach National 
Policy Influence Type Citation in clinical guidelines
URL http://www.bhiva.org/guidelines.aspx
 
Description Membership of University Public Engagement Advisory Board
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Participation in a advisory committee
 
Description NIHR Oxford BRC Renewal Round 3
Amount £320,000 (GBP)
Organisation Oxford University Hospitals NHS Foundation Trust 
Department NIHR Oxford Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start 04/2017 
End 04/2022
 
Description Public Engagement Grant
Amount £30,000 (GBP)
Organisation Viiv Healthcare 
Sector Private
Country United Kingdom
Start 01/2018 
End 06/2018
 
Description Public Engagement Grant
Amount £30,000 (GBP)
Organisation Gilead Sciences, Inc. 
Department Gilead
Sector Private
Country United Kingdom
Start 01/2018 
End 06/2018
 
Description RIO Clinical Trial: Set up award
Amount £90,267 (GBP)
Organisation Bill and Melinda Gates Foundation 
Sector Charity/Non Profit
Country United States
Start 10/2018 
End 09/2019
 
Description Using Genome Variation to Sort Extremely Rare Cell Populations for Clinical Application
Amount £59,529 (GBP)
Organisation Medical and Life Sciences Translational Fund 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2019 
End 03/2020
 
Title ATAC Seq 
Description Assay to determine transcriptional status of human genes. Assay was taught by collaborators at Harvard and work was carried out by a student GM in both Oxford and Harvard 
Type Of Material Technology assay or reagent 
Year Produced 2017 
Provided To Others? Yes  
Impact Paper submitted relating HIV therapy status and persistence to transcriptional activity 
 
Title PITCH sample repository 
Description Samples from participants undertaking antiretroviral therapy treatment interruptions 
Type Of Material Biological samples 
Year Produced 2018 
Provided To Others? Yes  
Impact Study on-going 
 
Title Single Genome HIV Proviral sequencing for bNAb sensitivity 
Description NGS assay to determine sensitivity of HIV isolates to bNAb neutralisation. Developed in collaboration with Rockefeller 
Type Of Material Technology assay or reagent 
Year Produced 2018 
Provided To Others? Yes  
Impact Identifying individuals who can receive bNAb therapy 
 
Title HEATHER database 
Description Collection of data regarding participants in the HEATHER HIV cohort 
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? No  
Impact NIl as yet. Research protocols deriving from the database in preparation. 
 
Title PITCH Database 
Description Database of HIV+ individuals undertaking treatment interruptions 
Type Of Material Database/Collection of data 
Year Produced 2019 
Provided To Others? Yes  
Impact Study on-going 
 
Description Imperial and King's College 
Organisation Imperial College London
Department Department of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Contribute expertise, patient recruitment, strategy and laboratory assays to this NIHR collaboration
Collaborator Contribution Contribute expertise, patient recruitment, strategy and laboratory assays to this NIHR collaboration. Part of the evolution of the CHERUB network
Impact Multiple publications (listed), new collaborations (eg Rockefeller - listed) and new funding (detailed)
Start Year 2014
 
Description Imperial and King's College 
Organisation King's College London
Department Division of Immunology, Infection & Inflammatory Diseases (DIIID)
Country United Kingdom 
Sector Academic/University 
PI Contribution Contribute expertise, patient recruitment, strategy and laboratory assays to this NIHR collaboration
Collaborator Contribution Contribute expertise, patient recruitment, strategy and laboratory assays to this NIHR collaboration. Part of the evolution of the CHERUB network
Impact Multiple publications (listed), new collaborations (eg Rockefeller - listed) and new funding (detailed)
Start Year 2014
 
Description RIO Clinical Trial 
Organisation Imperial College London
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution This is a new collaborative project funded by the Bill and Melinda Gates Foundation. Funding is pending but the grant is worth $6.5 million and should be confirmed by the end of March 2019. This is a collaboration between Oxford, Imperial and Rockefeller to run a clinical trial of neutralising antibody therapy to treat HIV in the UK.
Collaborator Contribution Rockefeller provides neutralising antibodies for the trial, Imperial provides clinical trial expertise and Oxford provides laboratory assays
Impact Set-up grant from BMGF Knowledge exchange for assays
Start Year 2018
 
Description RIO Clinical Trial 
Organisation Rockefeller University
Department Laboratory of Virology and Infectious Disease
Country United States 
Sector Academic/University 
PI Contribution This is a new collaborative project funded by the Bill and Melinda Gates Foundation. Funding is pending but the grant is worth $6.5 million and should be confirmed by the end of March 2019. This is a collaboration between Oxford, Imperial and Rockefeller to run a clinical trial of neutralising antibody therapy to treat HIV in the UK.
Collaborator Contribution Rockefeller provides neutralising antibodies for the trial, Imperial provides clinical trial expertise and Oxford provides laboratory assays
Impact Set-up grant from BMGF Knowledge exchange for assays
Start Year 2018
 
Description RIO Trial - Set Up award 
Organisation Rockefeller University
Country United States 
Sector Academic/University 
PI Contribution Sequence potential participants for the trial Develop the protocol
Collaborator Contribution Sponsorship Protocol development Knowledge exchange
Impact Knowledge exchange Assay development Development of full grant award
Start Year 2018
 
Description Rockefeller University 
Organisation Rockefeller University
Country United States 
Sector Academic/University 
PI Contribution Undertook screening of samples for antibody sensitiviries for clinical trial
Collaborator Contribution Developed technology and bioinformatics
Impact Grant funding Clinical trial
Start Year 2019
 
Title METHODS TO DETECT CELLS LATENTLY INFECTED WITH HIV 
Description The present invention provides a method of identifying a cell latently infected with HIV, wherein the method comprises: providing a sample of cells; encapsulating individual cells in droplets; screening for the presence of HIV derived DNA in the genomic DNA of encapsulated cells; and identifying, and optionally isolating, cells containing latent HIV derived DNA. 
IP Reference WO2019012270 
Protection Patent application published
Year Protection Granted 2019
Licensed No
Impact In process with OUI
 
Description BBC Radio Podcasts 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Podcasts of science interviews
Year(s) Of Engagement Activity 2019
 
Description CHELSEA FLOWER SHOW HIV STIGMA GARDEN 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Garden presented at RHS Chelsea 2018. Themed on HIV Stigma. Won Silver Guilt Award. Huge national and international media attention. Prime time BBC1 TV report on the garden as well as national and international TV and Radio coverage. Handed out 10,000 leaflets on site. Estimated audience greater than 3 million
Year(s) Of Engagement Activity 2018
URL https://www.medsci.ox.ac.uk/cherub-hiv-garden
 
Description HEATHER participant meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Study participants or study members
Results and Impact Patient group meeting at Imperial College for HEATHER cohort
Year(s) Of Engagement Activity 2015,2016,2017
 
Description Podcast on HIV cure 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Podcast as part of Wellcome Trust project with 'A Gay and a Non-Gay'
Year(s) Of Engagement Activity 2020
 
Description Podcast on HIV stigma and research 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Podcast on the history of HIV, stigma and the search for a cure
Year(s) Of Engagement Activity 2018
URL https://www.oxfordsparks.ox.ac.uk/content/can-you-cure-hiv
 
Description RIVER Trial Participant Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact To inform and educate participants about the RIVER trial and its outcomes
Year(s) Of Engagement Activity 2018
URL http://www.cherub.uk.net