What Constitutes a Protective CTL Response in HIV-1 Infection?

Lead Research Organisation: Imperial College London
Department Name: Dept of Medicine

Abstract

What constitutes a good immune response? Why do some HIV-infected people develop AIDS in months whilst others remain healthy for decades? How do your genes affect your outcome of infection? These are the fundamental questions that we are trying to answer.

The size of the HIV pandemic is staggering. In some areas of sub-Saharan Africa 1 in every 3 adults are infected. A cheap effective vaccine is desperately needed. The first step in designing an HIV vaccine is understanding the type of immunity that it should induce, i.e. what exactly is a good immune response?

Answering this question is complicated by the fact that HIV destroys immune cells. Consequently we cannot tell if immune response attributes associated with good viral control are a cause or an effect of low levels of virus. This means that many traditional methods of investigating the immune response are redundant.

A clue as to what determines the efficacy of the human immune response lies in the observation that some people naturally control HIV infection much better than others and that this is, in part, related to the person’s genetic makeup. The aim of this project is to understand what a good immune response is by understanding why some genes result in better immune control than others.

The research will be conducted by a novel mathematical analysis of existing HIV-infected patient databases. Our results will contribute to our understanding of what constitutes a good immune response. This could have direct implications for human health and HIV vaccine development. More generally, severity of illness for all 3 of the world’s most devastating diseases: AIDS, malaria and TB is partially determined by host genetics. We hope that the methods and insights our research generates will be applicable in all of these cases.

Technical Summary

AIM: To determine what constitutes a protective CTL response in HIV-1 infection.

APPROACH.
Host HLA class I genotype is significantly associated with the outcome of HIV-1 infection. We will perform a meta-analysis of existing experimental data from 3 patient cohorts to determine the mechanisms underlying this association.

RATIONALE.
Recent data has shown that HIV-1 damages the immune system within weeks of infection. Consequently, it is difficult to ascertain if many of the CTL attributes previously associated with good immune control e.g. proliferative capacity are the cause, or simply a passive consequence, of low viral load. With host genetic effects the direction of causality is unequivocal. Consequently, by investigating the mechanisms underlying HLA associations we directly investigate the attributes of a protective CTL response.

BACKGROUND.
HIV-1 continually evolves to escape the host CTL response. It has been hypothesised that escape contributes to AIDS progression but no clear relationship has been demonstrated. Consequently, it is not known whether HIV-1 escape from CTL is an epiphenomenon that might exacerbate disease progression in a few atypical cases or whether it is a significant driving force that leads to AIDS in the majority.

PRELIMINARY DATA.
We have demonstrated a relationship between HLA protection and viral escape. We found that CTLs restricted by alleles associated with slow progression to AIDS recognised epitopes where escape variants were weakly selected (P=0.008) and occurred infrequently (P=0.017). Epitopes presented by protective alleles were more likely to elicit a CD8+ T cell response (P=0.001, P=0.0007) and less likely to contain sequence variation (P=0.006). A third of HLA-associated AIDS risk was explained by the net selective advantage of escape variants. These results were found across all alleles and epitopes studied, suggesting a universal CTL-dependent mechanism of protection.

PROJECT.
These data are promising. They show that the strength of selection for escape is a significant determinant of CTL protection and describe why different HLA alleles are associated with different rates of AIDS progression. However, they do not explain what determines CTL selection and consequently cannot be used to guide vaccine design. Here we test hypotheses regarding the basis of the CTL protective effect we have observed; including the contribution of epitope plasticity, CTL breadth and viral attenuation.

SIGNIFICANCE.
A prerequisite for rational vaccine design is an understanding of the attributes of protective immunity. More generally, what constitutes a good CTL response and how HLA genotype impacts on CTLs are fundamental questions in biomedicine.

Publications

10 25 50
 
Description EU FP7 ITN
Amount £4,000,000 (GBP)
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 05/2013 
End 05/2018
 
Description Investigator Award
Amount £1,036,189 (GBP)
Funding ID 103865 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2014 
End 10/2019
 
Description PhD studentship
Amount £113,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2009 
End 09/2012
 
Description Project grant (co-I)
Amount £324,871 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2010 
End 10/2013
 
Description Short term prize fellowship
Amount £6,000 (GBP)
Organisation Japan Society for the Promotion of Science (JSPS) 
Sector Public
Country Japan
Start 10/2012 
End 03/2013
 
Description project grant
Amount £450,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2012 
End 10/2015
 
Description project grant
Amount £606,046 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2011 
End 10/2014
 
Description project grant
Amount £375,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2011 
End 03/2014
 
Title Tool to predict T cell epitopes 
Description Tool to predict T cell epitopes. Available on public repository 
Type Of Material Technology assay or reagent 
Year Produced 2015 
Provided To Others? Yes  
Impact current tests indicate that this is amongst the most accurate prediction software available. Likely to have far reaching consequences for epitope discovery and fundamental research. 
 
Title assay for quantifying CTL lysis 
Description close to physiological" assay for quantifying CTL lysis in humans 
Type Of Material Technology assay or reagent 
Year Produced 2006 
Provided To Others? Yes  
Impact this assay has been used by a number of groups to quantify CTL lysis in patients 
 
Title method to quantify CTL efficiency 
Description new method to quantify the strength of the CTL response in vivo in HIV/SIV infected humans and non-human primates. 
Type Of Material Data analysis technique 
Year Produced 2006 
Provided To Others? Yes  
Impact Now widely used by many groups. 
 
Title quantification of lymphocyte turnover 
Description model to analyse in vivo lymphocyte labelling data 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2006 
Provided To Others? Yes  
Impact this model is now widely used by the international scientific community to analyse BrdU and stable-isotope labelling data 
 
Description Bayesian stats 
Organisation University of Bordeaux
Department Department of Biostatistics
Country France 
Sector Academic/University 
PI Contribution contribution of novel hypothesis
Collaborator Contribution Provision of new techniques for data analysis
Impact published paper: PMID: 21408213 multidiciplinary: immunology, mathematics, statistics
Start Year 2007
 
Description HAART/depletion 
Organisation Emory University
Department Emory School of Medicine
Country United States 
Sector Academic/University 
PI Contribution Modelled data to understand why CD8+ T cells do not appear to decrease the lifespan of SIV-infected cells
Collaborator Contribution Provision of data from NHP models
Impact published paper (PMID:21990968). Multidisciplinary: experimental immunology and mathematics
Start Year 2009
 
Description I2M: Immunology, Imaging and Modelling 
Organisation University of Leeds
Department School of Mathematics Leeds
Country United Kingdom 
Sector Academic/University 
PI Contribution organised a number of workshops to facillitate collaboration and ideas sharing
Collaborator Contribution contributed to scientific network
Impact currently preparing a proposal for EU FP7 ITN invoving many members of the I2M network. Multidisciplinary: mathematics, immunology, imaging, computer science
Start Year 2008
 
Description KIR 
Organisation National Institutes of Health (NIH)
Department National Cancer Institute (NCI)
Country United States 
Sector Public 
PI Contribution Modelled human immunogenetic data
Collaborator Contribution Intellectual input
Impact paper PMID: 22022261 multidiciplinary: genetics, mathematics, bioinformatics
Start Year 2010
 
Description NHP 
Organisation Harvard University
Department Harvard T.H. Chan School of Public Health
Country United States 
Sector Academic/University 
PI Contribution Model data to quantify the relative importance of different arms of the immune response
Collaborator Contribution Provision of data from SIV-infected macaques
Impact published paper: PMID: 21408213 multidiciplinary: immunology, mathematics, statistics
Start Year 2008
 
Description Robert Busch 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution We will provide mathematical modelling expertise which, combined with Dr Busch's new highly sensitive GC/MS techniques will enable the quantification of turnover of rare cell subsets in vivo
Collaborator Contribution Dr Busch is providing technical guidance on high sensitivity mass spec techniques
Impact grant submitted to Wellcome Trust. Multidisciplinary: mathematics, immunology, biochemistry
Start Year 2011
 
Description Beautiful Science 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Organising a project in which scientists and artists are working together to exhibit artistic representations of science.

Exhibitions planned for 2012
http://www.beautifulscience.info/
Year(s) Of Engagement Activity 2011
URL http://www.beautifulscience.info/
 
Description Beautiful Science contd 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Science-art exhibition at Brick Lane Gallery for 1 week.
Schools event attended by about 30 school children.
Public debate.

Very positive feedback. This project has been invited to the Oxford Science Festival, adopted for Faculty Support, adopted by the college as an umbrella for the college's public engagement activities
Year(s) Of Engagement Activity 2012
 
Description Invited chapter in a book 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact invited author of chapter in textbook for undergraduates and postgraduates (Mathematical models in biology)

popular book
Year(s) Of Engagement Activity 2008,2009
 
Description Invited speaker at International Conferences 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Royal Society Frontiers of Science, India 2008 audience: scientists from other disciplines

Disseminated research to non-specialist audience
Year(s) Of Engagement Activity 2008
 
Description invited presentations 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Invited to present at approximately 15 conferences/ universities. Audiences upto about 600.

Generated large amount of interest in my work
Year(s) Of Engagement Activity 2012
 
Description work with schoolchildren in London 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact prepared work aimed at explaining to year 12/13 students the use of mathematics in biology. As a running example we explain how theoretical immunology contributed to a better understanding and treatment of HIV-infection, providing background information on the HIV epidemic, the role of immunology in the disease and how to describe a (biological) system in equations.

Two school pupils worked with us in the department on a mini-research project, culminating in written and oral presentation of their results
Year(s) Of Engagement Activity 2009,2010