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Despite Biased TRBV Gene Usage against a Dominant HLA B57-Restricted Epitope, TCR Diversity Can Provide Recognition of Circulating Epitope Variants^1,2

Brenna C. Simons^*, Scott E. VanCompernolle^*,, Rita M. Smith, Jie Wei, Louise Barnett, Shelly L. Lorey, Dirk Meyer-Olson^, and Spyros A. Kalams^3,*,

^* Department of Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee 37232; Department of Medicine, Division of Infectious Disease, Vanderbilt University, Nashville, Tennessee 37232; and Abteilung Klinische Immunologie, Medizinische Hochschule Hannover, Hanover, Germany

The role of epitope-specific TCR repertoire diversity in the control of HIV-1 viremia is unknown. Further analysis at the clonotype level is important for understanding the structural aspects of the HIV-1 specific repertoire that directly relate to CTL function and ability to suppress viral replication. In this study, we performed in-depth analysis of T cell clonotypes directed against a dominantly recognized HLA B57-restricted epitope (KAFSPEVIPMF; KF11) and identified common usage of the TCR β-chain TRBV7 in eight of nine HLA B57 subjects examined, regardless of HLA B57 subtype. Despite this convergent TCR gene usage, structural and functional assays demonstrated no substantial difference in functional or structural avidity between TRBV7 and non-TRBV7 clonotypes and this epitopic peptide. In a subject where TRBV7-usage did not confer cross-reactivity against the dominant autologous sequence variant, another circulating TCR clonotype was able to preferentially recognize the variant peptide. These data demonstrate that despite selective recruitment of TCR for a conserved epitope over the course of chronic HIV-1 infection, TCR repertoire diversity may benefit the host through the ability to recognize circulating epitope variants.

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 National Institutes of Health grant AI39966 (S.A.K.), National Institutes of Health Training Grant 5T32HL069765-05, National Institutes of Health Training Grant 5T32A1060571-03, and the Vanderbilt-Meharry Center for AIDS Research (P30 AI54999). S.A.K. is an Elizabeth Glaser Scholar of the Elizabeth Glaser Pediatric AIDS Foundation.

² ELISPOT analyses were performed in the VMC Flow Cytometry and Immunology Shared Resource. The VMC Flow Cytometry and Immunology Core Shared Resource is supported by the Vanderbilt Ingram Cancer Center (P30 CA68485) and the Vanderbilt Digestive Disease Research Center (DK058404). Live cell sorting was performed in the Vanderbilt-Meharry CFAR Immunopathogenesis Core (P30 AI54999).

³ Address correspondence and reprint requests to Dr. Spyros Kalams, Department of Medicine, Division of Infectious Disease, Vanderbilt University, Medical Center North A2100, 1161 21st Avenue South, Nashville, TN 37232. E-mail address: spyros.a.kalams{at}vanderbilt.edu

⁴ Abbreviations used in this paper: TRBV, TCR variable region β; SFC, Spot forming cell.

⁵ The online version of this article contains supplemental material.