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

• 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
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.168.6.3099

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.