Objectives: Although CD8+ T cells play a critical role in the control of HIV-1 infection, their antiviral efficacy can be limited by antigenic variation and immune exhaustion. The latter phenomenon is characterized by the upregulation of multiple inhibitory receptors, such as programmed death-1 (PD-1), CD244 and lymphocyte activation gene-3 (LAG-3), which modulate the functional capabilities of CD8+ T cells.
Design and methods: Here, we used an array of different human leukocyte antigen (HLA)-B*15 : 03 and HLA-B*42 : 01 tetramers to characterize inhibitory receptor expression as a function of differentiation on HIV-1-specific CD8+ T-cell populations (n = 128) spanning 11 different epitope targets.
Results: Expression levels of PD-1, but not CD244 or LAG-3, varied substantially across epitope specificities both within and between individuals. Differential expression of PD-1 on T-cell receptor (TCR) clonotypes within individual HIV-1-specific CD8+ T-cell populations was also apparent, independent of clonal dominance hierarchies. Positive correlations were detected between PD-1 expression and plasma viral load, which were reinforced by stratification for epitope sequence stability and dictated by effector memory CD8+ T cells.
Conclusion: Collectively, these data suggest that PD-1 expression on HIV-1-specific CD8+ T cells tracks antigen load at the level of epitope specificity and TCR clonotype usage. These findings are important because they provide evidence that PD-1 expression levels are influenced by peptide/HLA class I antigen exposure.
aDepartment of Paediatrics, University of Oxford, Peter Medawar Building, Oxford
bInstitute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, United Kingdom
cDepartment of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen N, Denmark
dDepartment of Sexual Health, Royal Berkshire Hospital, Reading
eDepartment of Genitourinary Medicine, Northamptonshire Healthcare National Health Service Trust, Northampton General Hospital, Cliftonville, Northampton
fDepartment of Sexual Health, Wycombe Hospital, High Wycombe, Buckinghamshire
gThe Peter Medawar Building for Pathogen Research and NIHR Biomedical Research Centre, University of Oxford, South Parks Road, Oxford, United Kingdom
hKwaZulu-Natal Research Institute for Tuberculosis and HIV, K-RITH, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
iHuman Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
*David A. Price and Philip Goulder contributed equally to this study.
Correspondence to Henrik N. Kløverpris, KwaZulu-Natal Research Institute for Tuberculosis and HIV, K-RITH, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban 4001, South Africa. Tel: +27 31 260 4136; fax: +27 31 260 4203; e-mail: email@example.com
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Received February 18, 2014
Received in revised form May 21, 2014
Accepted May 22, 2014