Imperial College London
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ProfessorJonathanWeber

Faculty of Medicine, Department of Infectious Disease

Director of the AHSC, Professor of Communicable Diseases
 
 
 
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Contact

 

+44 (0)20 7594 3905j.weber

 
 
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Assistant

 

Mrs Siobhan Pigott +44 (0)20 7594 3901

 
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Location

 

2.15Faculty BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Hoffmann:2016:10.1371/journal.ppat.1005661,
author = {Hoffmann, M and Pantazis, N and Martin, GE and Hickling, S and Hurst, J and Meyerowitz, J and Willberg, CB and Robinson, N and Brown, H and Fisher, M and Kinloch, S and Babiker, A and Weber, J and Nwokolo, N and Fox, J and Fidler, S and Phillips, R and Frater, J and SPARTAC, and CHERUB Investigators},
doi = {10.1371/journal.ppat.1005661},
journal = {PLOS Pathogens},
title = {Exhaustion of Activated CD8 T Cells Predicts Disease Progression in Primary HIV-1 Infection},
url = {http://dx.doi.org/10.1371/journal.ppat.1005661},
volume = {12},
year = {2016}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - The rate at which HIV-1 infected individuals progress to AIDS is highly variable and impacted by T cell immunity. CD8 T cell inhibitory molecules are up-regulated in HIV-1 infection and associate with immune dysfunction. We evaluated participants (n = 122) recruited to the SPARTAC randomised clinical trial to determine whether CD8 T cell exhaustion markers PD-1, Lag-3 and Tim-3 were associated with immune activation and disease progression. Expression of PD-1, Tim-3, Lag-3 and CD38 on CD8 T cells from the closest pre-therapy time-point to seroconversion was measured by flow cytometry, and correlated with surrogate markers of HIV-1 disease (HIV-1 plasma viral load (pVL) and CD4 T cell count) and the trial endpoint (time to CD4 count <350 cells/μl or initiation of antiretroviral therapy). To explore the functional significance of these markers, co-expression of Eomes, T-bet and CD39 was assessed. Expression of PD-1 on CD8 and CD38 CD8 T cells correlated with pVL and CD4 count at baseline, and predicted time to the trial endpoint. Lag-3 expression was associated with pVL but not CD4 count. For all exhaustion markers, expression of CD38 on CD8 T cells increased the strength of associations. In Cox models, progression to the trial endpoint was most marked for PD-1/CD38 co-expressing cells, with evidence for a stronger effect within 12 weeks from confirmed diagnosis of PHI. The effect of PD-1 and Lag-3 expression on CD8 T cells retained statistical significance in Cox proportional hazards models including antiretroviral therapy and CD4 count, but not pVL as co-variants. Expression of 'exhaustion' or 'immune checkpoint' markers in early HIV-1 infection is associated with clinical progression and is impacted by immune activation and the duration of infection. New markers to identify exhausted T cells and novel interventions to reverse exhaustion may inform the development of novel immunotherapeutic approaches.
AU  - Hoffmann,M
AU  - Pantazis,N
AU  - Martin,GE
AU  - Hickling,S
AU  - Hurst,J
AU  - Meyerowitz,J
AU  - Willberg,CB
AU  - Robinson,N
AU  - Brown,H
AU  - Fisher,M
AU  - Kinloch,S
AU  - Babiker,A
AU  - Weber,J
AU  - Nwokolo,N
AU  - Fox,J
AU  - Fidler,S
AU  - Phillips,R
AU  - Frater,J
AU  - SPARTAC,and CHERUB Investigators
DO  - 10.1371/journal.ppat.1005661
PY  - 2016///
SN  - 1553-7366
TI  - Exhaustion of Activated CD8 T Cells Predicts Disease Progression in Primary HIV-1 Infection
T2  - PLOS Pathogens
UR  - http://dx.doi.org/10.1371/journal.ppat.1005661
UR  - http://hdl.handle.net/10044/1/38414
VL  - 12
ER  -
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