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* Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201;
Department of Biological Sciences, University of Texas, El Paso, TX 79968;
Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Weatherall Institute of Molecular Medicine, University of Oxford, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, United Kingdom;
¶ Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02192;
|| Department of Medicine and AIDS Institute, Center for Health Sciences, University of California, Los Angeles, CA 90095;
# Department of Microbiology and Immunology and
** Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York 10461;
Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261;
* Section of Immunogenetics, Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD 20892; and
* Department of Medical Biochemistry and Immunology, Cardiff University, Cardiff, Wales, United Kingdom
HLA-A2-restricted CTL responses to immunodominant HIV-1 epitopes do not appear to be very effective in the control of viral replication in vivo. In this study, we studied human CD8+ T cell responses to the subdominant HLA-A2-restricted epitope TV9 (Gag p2419–27, TLNAWVKVV) to explore the possibility of increasing its immune recognition. We confirmed in a cohort of 313 patients, infected by clade B or clade C viruses, that TV9 is rarely recognized. Of interest, the functional sensitivity of the TV9 response can be relatively high. The potential T cell repertoires for TV9 and the characteristics of constituent clonotypes were assessed by ex vivo priming of circulating CD8+ T cells from healthy seronegative donors. TV9-specific CTLs capable of suppressing viral replication in vitro were readily generated, suggesting that the cognate T cell repertoire is not limiting. However, these cultures contained multiple discrete populations with a range of binding avidities for the TV9 tetramer and correspondingly distinct functional dependencies on the CD8 coreceptor. The lack of dominant clonotypes was not affected by the stage of maturation of the priming dendritic cells. Cultures primed by dendritic cells transduced to present endogenous TV9 were also incapable of clonal maturation. Thus, a diffuse TCR repertoire appeared to be an intrinsic characteristic of TV9-specific responses. These data indicate that subdominance is not a function of poor immunogenicity, cognate TCR repertoire availability, or the potential avidity properties thereof, but rather suggest that useful responses to this epitope are suppressed by competing CD8+ T cell populations during HIV-1 infection.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Michigan Life Sciences Corridor Program 1659 (to J.K.-M.) and National Institutes of Health Grant R01-AI064069 (to J.K.-M.) and made possible by Grant 5G12RR008124 from the National Center for Research Resources, a component of the National Institutes of Health. D.A.P. is a Medical Research Council (U.K.) Senior Clinical Fellow.
2 Address correspondence and reprint requests to Dr. June Kan-Mitchell, Biological Sciences Building, University of Texas, 500 West University Avenue, El Paso, TX 79968. E-mail address: jkanmitchell{at}utep.edu
3 Abbreviations used in this paper: DC, dendritic cell; iDC, immature DC; mDC, matured DC; pMHCI, peptide MHC class I; sfc, spot-forming cell; tetramer, tetrameric HLA-A*0201-peptide complex; TV9, HIV-1 p24 Gag19–27 epitope (TLNAWVKVV); OLP, overlapping peptide.
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