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*
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, and
Department of Experimental Transplantation and Immunology, Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
MegaBases Inc., Northwestern University, Evanston Research Park, IL 60201; and
University of Texas Southwestern Medical Center, Dallas, TX 75390
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.
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S. A. Migueles, A. C. Laborico, H. Imamichi, W. L. Shupert, C. Royce, M. McLaughlin, L. Ehler, J. Metcalf, S. Liu, C. W. Hallahan, et al. The Differential Ability of HLA B*5701+ Long-Term Nonprogressors and Progressors To Restrict Human Immunodeficiency Virus Replication Is Not Caused by Loss of Recognition of Autologous Viral gag Sequences J. Virol., June 15, 2003; 77(12): 6889 - 6898. [Abstract] [Full Text] [PDF]
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O. O. Yang, P. T. N. Sarkis, A. Ali, J. D. Harlow, C. Brander, S. A. Kalams, and B. D. Walker Determinants of HIV-1 Mutational Escape From Cytotoxic T Lymphocytes J. Exp. Med., May 19, 2003; 197(10): 1365 - 1375. [Abstract] [Full Text] [PDF]
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D. Meyer-Olson, K. W. Brady, J. T. Blackard, T. M. Allen, S. Islam, N. H. Shoukry, K. Hartman, C. M. Walker, and S. A. Kalams Analysis of the TCR {beta} Variable Gene Repertoire in Chimpanzees: Identification of Functional Homologs to Human Pseudogenes J. Immunol., April 15, 2003; 170(8): 4161 - 4169. [Abstract] [Full Text] [PDF]
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J. Michalek, R. H. Collins, H. P. Durrani, P. Vaclavkova, L. E. Ruff, D. C. Douek, and E. S. Vitetta Definitive separation of graft-versus-leukemia- and graft-versus-host-specific CD4+ T cells by virtue of their receptor beta loci sequences PNAS, February 4, 2003; 100(3): 1180 - 1184. [Abstract] [Full Text] [PDF]
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A. D. Bitmansour, D. C. Douek, V. C. Maino, and L. J. Picker Direct Ex Vivo Analysis of Human CD4+ Memory T Cell Activation Requirements at the Single Clonotype Level J. Immunol., August 1, 2002; 169(3): 1207 - 1218. [Abstract] [Full Text] [PDF]
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