The Impact of T Cell Immunity on HIV-1 Diversity

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

Abstract

Despite intensive research there is still no effective HIV vaccine. There has been a recent international call to suspend clinical vaccine trials and to concentrate on the underlying molecular biology that determines how and why a vaccine might succeed. This project aims to address these fundamental issues.

HIV has the ability to adapt to its environment in a manner unprecedented in any other organism. This is reflected by the rapid development of resistance to antiviral drugs and by the development of mutations that camouflage the virus from the immune system. This project will demonstrate how, in a population of newly infected HIV positive individuals, the virus that has been transmitted will adapt to a key component of the immune system of the new host and simultaneously revert many of the mutations acquired during infection of the previous host. As patients progress to AIDS we hope to show how the immune system is no longer able to exert any selection pressure on the virus.

We will explore the key components of our immune system to see whether adaptation to one may be disadvantageous to others. If so, the impact of viral evolution on the efficacy of our immune system may be more significant than realised.

Technical Summary

Aims
This project aims to determine the degree to which HIV is evolving at the population level to adapt to the human immune system.
Objectives
To explore the impact of HLA on the long-term evolution of HIV within a population.
o To define the evolution of HLA-associated genetic diversity from the time of infection until established chronic infection by tracking HIV sequence variation in a strictly defined group of several hundred seroconverters.
o To study how the onset of AIDS impacts on the fate of HLA-associated viral mutations.
To test whether identified polymorphisms facilitate adaptation to both HLA Class I subtypes and ‘supertypes‘.
o To assess the functional significance of identified polymorphisms using assays of HLA Class I binding and T cell activation.
o To identify cross-recognition of HIV-1 antigens by multiple HLA Class I subtypes according to the principle of ‘supertypes‘.
Design
This project will investigate a unique group of predominantly untreated HIV seroconverters that will represent the largest studied cohort of this sort to date. The study will involve both longitudinal and cross-sectional analyses. Stored samples will be tested retrospectively and those from newly recruited patients, prospectively.

Methodology
We have established collaborations to study four independent patient cohorts. Samples from HIV seroconverters will be tested retrospectively from St. Mary‘s Hospital in London (n=105) and from the Swiss HIV cohort (n=100). In addition, new patients will be recruited prospectively from the ‘Spartac‘ seroconverter cohort (total predicted n=450). Chronically infected HIV+ve patients will be recruited from the Free State ARV programme in South Africa (n>2000).

Longitudinal sequence analysis of viral RNA and proviral DNA by population and clonal sequencing will identify patterns of mutation and reversion and, specifically, the evolution of association of HIV polymorphisms with Class I HLA molecules. Bindi assess the interaction between variant peptides and HLA Class I molecules. Functional assays ( -interferon ELISpot) will be used to study the ability of variant peptides to induce an immune response.

Scientific and Medical Opportunities
The project will provide a detailed description of the HIV antigenic challenge. We will gain understanding of the population level evolution of HIV with inferences for changes in pathogenesis of the epidemic. The detailed sequence data will contribute towards understanding the HIV response to vaccine challenge - crucial information that is currently being demanded at an international level to enable the design of a sustainable vaccine.

Publications

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publication icon
SPARTAC Trial Investigators (2013) Short-course antiretroviral therapy in primary HIV infection. in The New England journal of medicine

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Williams JP (2012) Current understanding in HIV immunopathology and treatment. in QJM : monthly journal of the Association of Physicians

 
Guideline Title BHIVA Treatment Guidelines
Description British HIV Association treatment guidelines 2015
Geographic Reach National 
Policy Influence Type Citation in clinical guidelines
URL http://WWW.BHIVA.ORG
 
Description Chief Medical Officer Policy Meeting
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description Engagement with iBase
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Impact PAtient and public education around HIV from the ibase publication, website and Twitter feed
 
Description BHIVA Research Award
Amount £30,000 (GBP)
Organisation British HIV Association (BHIVA) 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2013 
End 11/2015
 
Description James Martin 21st Century School
Amount £512,000 (GBP)
Organisation University of Oxford 
Department James Martin 21st Century School
Sector Academic/University
Country United Kingdom
Start 07/2012 
End 06/2015
 
Description John Fell Fund
Amount £79,590 (GBP)
Organisation University of Oxford 
Department John Fell Fund
Sector Academic/University
Country United Kingdom
Start 05/2013 
End 04/2015
 
Description John Fell Fund, Oxford University Press/Oxford University Press
Amount £48,000 (GBP)
Organisation University of Oxford 
Department John Fell Fund
Sector Academic/University
Country United Kingdom
Start 03/2006 
End 02/2007
 
Description MRC CiC
Amount £53,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2013 
End 04/2014
 
Description MRC DCS
Amount £1,700,000 (GBP)
Funding ID MR/L00528X/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 11/2014 
End 10/2017
 
Description MRC Senior Clinical Fellowship
Amount £1,800,000 (GBP)
Funding ID MR/L006588/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2014 
End 09/2019
 
Description NIHR OXFORD CBRC RENEWAL
Amount £95,000,000 (GBP)
Organisation Oxford University Hospitals NHS Foundation Trust 
Department NIHR Oxford Biomedical Research Centre
Sector Public
Country United Kingdom
Start 04/2012 
End 04/2017
 
Description Nuffield Dept of Medicine Studentship
Amount £64,000 (GBP)
Organisation University of Oxford 
Department Nuffield Department of Medicine
Sector Academic/University
Country United Kingdom
Start 10/2010 
End 09/2014
 
Description Nuffield Dept of Medicine Studentship (for JM, DPhil Student)
Amount £65,900 (GBP)
Organisation University of Oxford 
Department Nuffield Department of Medicine
Sector Academic/University
Country United Kingdom
Start 10/2009 
End 09/2013
 
Description Oxford Biomedical Research Council/Oxford NIHR CBRC
Amount £20,000 (GBP)
Organisation Oxford University Hospitals NHS Foundation Trust 
Department NIHR Oxford Biomedical Research Centre
Sector Public
Country United Kingdom
Start 04/2010 
End 04/2011
 
Description Rhodes Scholarship (For GH, DPhil Student)
Amount £65,000 (GBP)
Organisation Rhodes Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2006 
End 09/2010
 
Description Rhodes Scholarship (for LM, DPhil Student)
Amount £64,000 (GBP)
Organisation Rhodes Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2010 
End 09/2014
 
Title Acute HIV samples DNA library 
Description Repository of 360 samples of plasma and PBMC from acutely infected HIV+ve individuals developed in conjunction with the Wellcome-funded SPARTC trial 
Type Of Material Biological samples 
Year Produced 2009 
Provided To Others? Yes  
Impact With have already published and presented data on early within host and between host HIV adaptation, made possible through this repository. This culminated in a paper in Nature in 2009 (Kawashima et al) 
 
Title Bloemfontein sample repository of plasma from AIDS patients 
Description A repository of around 800 plasma samples from patients in Bloemfontein, South Africa at different stages of HIV clinical progression. 
Type Of Material Biological samples 
Year Produced 2010 
Provided To Others? Yes  
Impact FIve papers resulting from this, including Carlson et al Science 2014 
 
Title CHERUB Collaboration 
Description NIHR funded pan-CBRC cooperative across Oxford, Cambridge, Imperial, UCL and King's with international networks and industry engagement 
Type Of Material Improvements to research infrastructure 
Year Produced 2011 
Provided To Others? Yes  
Impact Funding in NIHR renewal in 2011 across all five CBRCs for CHERUB infrastructure Pan-CBRC collaboration between UCL, OXford, Cambridge, King's and Imperial 
 
Title Droplet Digitial PCR Open Source Software 
Description On-line software to interpret raw data from digital droplet PCR 
Type Of Material Technology assay or reagent 
Year Produced 2013 
Provided To Others? Yes  
Impact Improved low copy calling of ddPCR outputs Most downloaded paper in J Virol Methods for first 6 months of 2014 
URL http://definetherain.org.uk/
 
Title HIV sequence databases 
Description Database of HIV viral sequences obtained from acutely infected patients (SPARTAC) and end-stage patients (Bloemfontein). 
Type Of Material Biological samples 
Year Produced 2010 
Provided To Others? Yes  
Impact A number of publications and presentations - all referenced in the publications section. Collaborations and publications resulting particularly with Goulder and Carlsson 
 
Title SPARTAC PBMC Repository 
Description PBMCs from the SPARTAC trial 
Type Of Material Biological samples 
Year Produced 2010 
Provided To Others? Yes  
Impact Publications, documented in portfolio 
 
Title Definetherain 
Description Open source software to analyse digital droplet PCR data 
Type Of Material Data analysis technique 
Year Produced 2013 
Provided To Others? Yes  
Impact Most downloaded paper from J Virol Methods for first 6 months of 2014 
 
Description Adaptimmune Ltd 
Organisation Adaptimmune
Country United Kingdom 
Sector Private 
PI Contribution Industry partner. Utilisation of partner's reagents and facilities to expand primary cell models of latency and proof-of-concept strategies for novel HIV interventions.
Collaborator Contribution Industry Partner Collaboration to provide reagents and services. Services include mass spectrometry and T cell line preparation Reagents include Adapted TCRs and viral vectors
Impact MRC Confidence in Concept award - 2013 No publications as yet, although work in progress
Start Year 2012
 
Description CHERUB Cooperative: Collaborative HIV Eradication of Reservoirs: UK BRC 
Organisation Imperial College London
Department Department of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution I am the chair of the CHERUB TSC, the scientific lead and overall co-PI. CHERUB infrastructure has been funded across all five CBRCs as part of a 5-way cooperative agreement
Collaborator Contribution Academic, strategy and intellectual input
Impact Initially funding from the NIHR CBRC renewal across all five CBRCS
Start Year 2010
 
Description Gilead 
Organisation Gilead Sciences, Inc.
Department Gilead
Country United Kingdom 
Sector Private 
PI Contribution Investigation of novel anti-HIV therapy
Collaborator Contribution Provision of novel anti-HIV therapy under MTA
Impact Work in progress
Start Year 2012
 
Description Harvard Medical School 
Organisation Harvard University
Department Harvard Medical School
Country United States 
Sector Academic/University 
PI Contribution Provision of reagents for viral fitness assays and collaborative research
Collaborator Contribution Facilitated on-going research project into HIV viral fitness
Impact DPhil achieved for Gary Huang, under my supervision. Publication: Progression to AIDS in South Africa is associated with both reverting and compensatory viral mutations. Huang KH, Goedhals D, Carlson JM, Brockman MA, Mishra S, Brumme ZL, Hickling S, Tang CS, Miura T, Seebregts C, Heckerman D, Ndung'u T, Walker B, Klenerman P, Steyn D, Goulder P, Phillips R; Bloemfontein-Oxford Collaborative Group, van Vuuren C, Frater J. PLoS One. 2011 Apr 22;6(4):e19018. doi: 10.1371/journal.pone.0019018. PMID: 21544209
Start Year 2009
 
Description MRC CTU: UK Register of Seroconverters 
Organisation Medical Research Council (MRC)
Department MRC Clinical Trials Unit
Country United Kingdom 
Sector Public 
PI Contribution Collaboration with MRC CTU to analyse HIV reservoir levels in patients with primary HIV infection
Collaborator Contribution To identify and trace potential participants to the UK Heather cohort
Impact BHIVA Research Award - £30,000 MRC Senior Fellowship
Start Year 2013
 
Description Merck & Co 
Organisation Merck
Department Infectious Disease and Antimicrobial Resistance
Country United States 
Sector Private 
PI Contribution Investigation of novel anti-HIV therapy
Collaborator Contribution Provision via MTA of novel anti-HIV therapy
Impact Recent MRC DCS award ('REACH') in which MERCK is an industry partner
Start Year 2012
 
Description Microsoft 
Organisation Microsoft Research
Department eScience
Country United Kingdom 
Sector Private 
PI Contribution Sharing of data and analytical techniques
Collaborator Contribution Research outputs, conference abstracts. Paper in review
Impact Research outputs (Conference presentation, DPhil). Paper currently in review
Start Year 2009
 
Description Oxford Martin School 
Organisation University of Oxford
Department James Martin 21st Century School
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration stemming from the Institute of Emerging Infection and resulting in a new round of funding won through a competitive process
Collaborator Contribution Development of software pipelines and sequencing technologies to inform HIV and HCV cure strategies
Impact On-going publications from Institute of Emerging Infections, documented in publications section of portfolio
Start Year 2012
 
Description Oxford-Bloemfontein Collaborative Group 
Organisation University of Free State, Bloemfontein
Country South Africa 
Sector Academic/University 
PI Contribution We have collaborated with the Free State University to recruit over 1500 patients to a study of viral evolution and drug resistance in patients with advanced HIV infection
Collaborator Contribution Recruitment of patients with late-stage AIDS infection to a study of viral adaptation in advanced disease
Impact Recent publication (19918101) in Antiviral Therapy and poster and oral presentations at national and international meetings
 
Description Royal Institution and UCL 
Organisation The Royal Institution of Great Britain
Country United Kingdom 
Sector Academic/University 
PI Contribution Analysis of reagents
Collaborator Contribution Provision of reagents
Impact Publication: Application of magnetic field hyperthermia and superparamagnetic iron oxide nanoparticles to HIV-1-specific T-cell cytotoxicity. Williams JP, Southern P, Lissina A, Christian HC, Sewell AK, Phillips R, Pankhurst Q, Frater J. Int J Nanomedicine. 2013;8:2543-54. doi: 10.2147/IJN.S44013. Epub 2013 Jul 23. PMID: 23901272
Start Year 2010
 
Description SPARTAC Trial Investigators 
Organisation Imperial College London
Department Imperial Clinical Trials Unit (ICTU)
Country United Kingdom 
Sector Academic/University 
PI Contribution My groups has collaborated with the SPARTAC investigators to determine the degree of HIV viral evolution and immune escape in acute and early HIV infection
Collaborator Contribution Access to samples taken from a large cohort of caucasian and African HIV seroconverters enrolled in a trial of short course therapy in acute infection
Impact We have recently published two papers in the journal of Virology (19019964, 17409157) as well as oral and poster presentations at a number of international meetings. The trial published this year in NEJM: PMID: 23323897
Start Year 2006
 
Description UPenn 
Organisation University of Pennsylvania
Country United States 
Sector Academic/University 
PI Contribution Assistance with HIV viral sequencing Training of lab member
Collaborator Contribution Training of DPhil student Assistance with development assays in the lab
Impact Williams et al; HIV Cure Symposium 2013; Oral Presentation Williams et al; IAS 2013; Kuala Lumpur; Oral Presentation
Start Year 2011
 
Description University of Melbourne 
Organisation University of Melbourne
Department Department of Microbiology and Immunology
Country Australia 
Sector Academic/University 
PI Contribution Implementation of viral RNA assay in the lab
Collaborator Contribution Training and provision of reagents
Impact Assay implemented and published
Start Year 2012
 
Title HDACi + Vaccination for HIV cure 
Description New use of combination therapy of HDAC inhibitors plus vaccination in primary HIV infection as a strategy to cure HIV. Funded by £1.7 million MRC DCS award. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2013
Development Status Under active development/distribution
Impact This combination of therapies is to be trialled in a clinical trial, with recruitment commencing in 2014 
 
Title HIV reservoir assays 
Description Assays to measure the HIV proviral load and ultra-low level viraemia for patients receiving antiretroviral therapy. Assays to be trialed over next 12-36 months for value in application to NHS clinic practice 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Initial development
Year Development Stage Completed 2011
Development Status Under active development/distribution
Impact Impact pending result of trials to test clinical relevance and application 
 
Title Definetherain 
Description Open source software for analysis of droplet digital PCR data 
Type Of Technology Software 
Year Produced 2013 
Open Source License? Yes  
Impact Widely accessed. Most downloaded J Virol Methods paper for early 2014 
 
Description Dalian Summer WEF 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact 100 business leaders, politicians, academics attended a talk and then a workshop led by me

Excellent feedback and expanded collaborations in non-medical community
Year(s) Of Engagement Activity 2013
 
Description Davos World Economic Forum 2013 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Invited to attend in 2012, for the meeting in January 2013. Presentation within a Think Tank for Oxford Martin School

Well received by delegates in academia and private sector
Year(s) Of Engagement Activity 2012
 
Description IAS Press Conference 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Press conference to inform international media of results of reservoir work from the SPARTAC trial and to inform on future work towards an HIV cure

Widespread media reporting eg:
http://www.hivandhepatitis.com/hiv-treatment/hiv-cure/4206-ias-2013-1the-future-of-hiv-cure-research-video
Year(s) Of Engagement Activity 2013
URL http://www.youtube.com/watch?v=Wo8NdKWVdhU
 
Description Oxford NIHR BRC Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Schools and members of the public visited the stall over the course of the day - at least 100 visitors - to learn about HIV, its treatment and drug resistance.

Broad engagement across schools and general public.
Year(s) Of Engagement Activity 2013
 
Description Radio Interview (5 Live 2012 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Radio interview on the state of the HIV epidemic in the UK

Reported by Oxford Martin school press release
Year(s) Of Engagement Activity 2012
 
Description Radio Interview 5 Live 2012 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Interview on HIV Cure research

Broad publicity for HIV cure research
Year(s) Of Engagement Activity 2012
 
Description Radio Scotland Interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Interview on HIV cure research

Broad publicity for research field
Year(s) Of Engagement Activity 2012
 
Description Royal Society Summer Science Exhibition 2010 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Schools
Results and Impact a 9 day festival of science with hundreds of school pupils and members of the public involved in discussion and interactive activities and games

Significant interest discussed in science and medicine amongst school groups
Year(s) Of Engagement Activity 2010
 
Description School Visit (Chiping Norton) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Schools
Results and Impact 150 students from GCSE to 6th form attended a talk on HIV research and a subsequent discussion on the epidemic

Have been asked to speak again and to a separate talk to the 'gifted and talented' student group.
Also asked to assist with med school interview preparation
Year(s) Of Engagement Activity 2013