title: 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.
abstract: 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.
authors.affiliation: Department of Experimental Transplantation and Immunology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. ddouek@mail.nih.gov
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: Michael R
authors.initials: MR
authors.lastname: Betts
authors.forename: Jason M
authors.initials: JM
authors.lastname: Brenchley
authors.forename: Brenna J
authors.initials: BJ
authors.lastname: Hill
authors.forename: David R
authors.initials: DR
authors.lastname: Ambrozak
authors.forename: Ka-Leung
authors.initials: KL
authors.lastname: Ngai
authors.forename: Nitin J
authors.initials: NJ
authors.lastname: Karandikar
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Casazza
authors.forename: Richard A
authors.initials: RA
authors.lastname: Koup
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology* / Q000821:virology*; D002999:Clone Cells; D018984:Epitopes, T-Lymphocyte / Q000032:analysis* / Q000235:genetics / Q000276:immunology; D006678:HIV / Q000276:immunology* / Q000502:physiology; D006801:Humans; D016056:Immunodominant Epitopes / Q000032:analysis / Q000276:immunology; D008137:Longitudinal Studies; D018655:Lymphocyte Count; D008875:Middle Aged; D008969:Molecular Sequence Data; D016693:Receptors, Antigen, T-Cell, alpha-beta; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014779:Virus Replication / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D016693:Receptors, Antigen, T-Cell, alpha-beta