A Novel Approach to the Analysis of Specificity, Clonality, and Frequency of HIV-Specific T Cell Responses Reveals a Potential Mechanism for Control of Viral Escape

Escape from the CD8(+) T cell response through epitope mutations can lead to loss of immune control of HIV replication. Theoretically, escape from CD8(+) T cell recognition is less likely when multiple TCRs target individual MHC/peptide complexes, thereby increasing the chance that amino acid change...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2002-03, Vol.168 (6), p.3099-3104
Main Authors: Douek, Daniel C, Betts, Michael R, Brenchley, Jason M, Hill, Brenna J, Ambrozak, David R, Ngai, Ka-Leung, Karandikar, Nitin J, Casazza, Joseph P, Koup, Richard A
Format: Article
Language:English
Subjects:
Adult
Aged
Amino Acid Sequence
CD8 antigen
CD8-Positive T-Lymphocytes - chemistry
CD8-Positive T-Lymphocytes - immunology
CD8-Positive T-Lymphocytes - virology
Clone Cells
Epitopes, T-Lymphocyte - analysis
Epitopes, T-Lymphocyte - genetics
Epitopes, T-Lymphocyte - immunology
HIV - immunology
HIV - physiology
Human immunodeficiency virus
Humans
Immunodominant Epitopes - analysis
Immunodominant Epitopes - immunology
Longitudinal Studies
Lymphocyte Count
Middle Aged
Molecular Sequence Data
Receptors, Antigen, T-Cell, alpha-beta
Reverse Transcriptase Polymerase Chain Reaction
Virus Replication - immunology
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Summary:Escape from the CD8(+) T cell response through epitope mutations can lead to loss of immune control of HIV replication. Theoretically, escape from CD8(+) T cell recognition is less likely when multiple TCRs target individual MHC/peptide complexes, thereby increasing the chance that amino acid changes in the epitope could be tolerated. We studied the CD8(+) T cell response to six immunodominant epitopes in five HIV-infected subjects using a novel approach combining peptide stimulation, cell surface cytokine capture, flow cytometric sorting, anchored RT-PCR, and real-time quantitative clonotypic TCR tracking. We found marked variability in the number of clonotypes targeting individual epitopes. One subject recognized a single epitope with six clonotypes, most of which were able to recognize and lyse cells expressing a major epitope variant that arose. Additionally, multiple clonotypes remained expanded during the course of infection, irrespective of epitope variant frequency. Thus, CD8(+) T cells comprising multiple TCR clonotypes may expand in vivo in response to individual epitopes, and may increase the ability of the response to recognize virus escape mutants.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.168.6.3099