NDLI: Generation of robust CD8+ T cell responses against subdominant epitopes in conserved regions of HIV-1 by repertoire mining with mimotopes

Content Provider	PubMed Central
Author	Schaubert, Keri L. Price, David A. Salkowitz, Janelle R. Sewell, Andrew K. Sidney, John Asher, Tedi E. Blondelle, Sylvie E. Adams, Sharon Marincola, Francesco M. Joseph, Aviva Sette, Alessandro Douek, Daniel C. Ayyavoo, Velpandi Walter, Storkus Leung, Ming-ying Ng, Hwee L. Yang, Otto O. Goldstein, Harris Wilson, Darcy B. June, Kan-mitchell
Abstract	HLA-A0201-restricted virus-specific CD8+ cytotoxic T lymphocytes (CTLs) do not appear to control HIV effectively in vivo. To enhance the immunogenicity of a highly conserved subdominant epitope, TV9 (TLNAWVKVV, p24 Gag19–27), mimotopes were designed by screening a large combinatorial nonapeptide library with TV9-specific CTLs primed in vitro from healthy donors. A mimic peptide with a low binding affinity to HLA-A0201, TV9p6 ( KI NAW I KVV), was studied further. Parallel cultures of in vitro-primed CTLs showed that TV9p6 consistently activated crossreactive and equally functional CTLs as measured by cytotoxicity, cytokine production and suppression of HIV replication in vitro. Comparison of TCRB gene usage between CTLs primed from the same donors with TV9 or TV9p6 revealed a degree of clonal overlap in some cases and an example of a conserved TCRB sequence encoded distinctly at the nucleotide level between individuals (a “public” TCR); however, in the main, distinct clonotypes were recruited by each peptide antigen. These findings indicate that mimotopes can mobilize functional crossreactive clonotypes that are less readily recruited from the naïve T cell pool by the corresponding wildtype epitope. Mimotope-induced repertoire diversification could potentially override subdominance under certain circumstances and enhance vaccine-induced responses to conserved but poorly immunogenic determinants within the HIV proteome.
Related Links	http://dx.doi.org/10.1002/eji.200940079
Ending Page	1962
Page Count	13
Starting Page	1950
File Format	PDF
ISSN	00142980
e-ISSN	15214141
Journal	European journal of immunology
Issue Number	7
Volume Number	40
Language	English
Publisher Date	2010-07-01
Access Restriction	Open
Subject Keyword	Immunology Immunology and Allergy Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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