106. A Novel Approach to the Analysis of Specificity, Clonality, and Frequency of HIV-Specific T-Cell Responses Reveals a Mechanism for Lack of Escape within an Immunodominant Epitope

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Session 25 Oral Abstract Session
Immunology
Session Time: Wednesday, 10 am - 12:30 pm
Room 6C

11:15 106.

A Novel Approach to the Analysis of Specificity, Clonality, and Frequency of HIV-Specific T-Cell Responses Reveals a Mechanism for Lack of Escape within an Immunodominant Epitope
D. Douek^*1, M. Betts¹, J. Brenchley¹, B. Hill¹, D. Ambrozak¹, K. L. Ngai², J. Casazza³, and R. Koup¹
¹NIAID Vaccine Res. Ctr., NIH, Bethesda, MD; ²MegaBases, Inc., Northwestern Univ., Chicago, IL; and ³Univ. of Texas Southwestern Med. Ctr., Dallas

Background: Escape from the CD8+ T-cell response through mutations within encoded epitopes can lead to loss of immune control of human immunodeficiency virus (HIV) replication. Theoretically, escape from CD8+ T cell recognition is less likely when multiple T-cell receptors (TCR) target individual MHC/peptide complexes, thereby increasing the chance that amino acid changes in the epitope could be tolerated.
Methods: We studied the CD8+ T-cell response to 6 immunodominant epitopes in 5 HIV-infected subjects using a novel approach that combined peptide stimulation, cell surface cytokine capture, flow cytometric sorting, anchored TCR reverse-transcription (RT)-PCR, and real-time quantitative clonotypic TCR tracking.
Results: We found great variability in the number of TCR that targeted individual epitopes. For example, in 1 subject a single TCR clonotype was expanded in response to 1 epitope, while 15 TCR clonotypes were expanded in response to a different epitope. 1 subject recognized a single epitope in which variants arose, but did not go on to dominate the viral population. We found that 6 TCR clonotypes targeted this epitope, most of which were able to recognize and lyse cells expressing the major epitope variant. Additionally, multiple TCR clonotypes remained expanded throughout the course of infection, irrespective of epitope variant frequency.
Conclusions: These results indicate that CD8+ T cells comprising multiple TCR clonotypes may expand in vivo in response to individual epitopes, and may limit the ability of the virus to escape CD8+ T cell recognition.

Š2002 9^th Conference on Retroviruses and Opportunistic Infections