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Blood, 15 March 2006, Vol. 107, No. 6, pp. 2373-2383.
Prepublished online as a Blood First Edition Paper on December 1, 2005; DOI 10.1182/blood-2005-04-1636.
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Submitted April 22, 2005
Accepted October 27, 2005
Fluctuations of functionally distinct CD8+ T cell clonotypes demonstrate flexibility of the HIV-specific TCR repertoire
Dirk Meyer-Olson, Kristen W Brady, Melissa T Bartman, Kristin M O'Sullivan, Brenna C Simons, Joseph A Conrad, Coley B Duncan, Shelly Lorey, Atif Siddique, Rika A Draenert, Marylyn Addo, Marcus Altfeld, Eric Rosenberg, Todd M Allen, Bruce D Walker, and Spyros A Kalams*
Department of Medicine, Vanderbilt University Medical Center, Infectious Diseases Unit, Nashville, TN, USA; Partners AIDS Research Center, Harvard Medical School & Massachusetts General Hospital, Boston, MA, Germany; Medizinische Hochschule Hannover, Abteilung Klinische Immunologie, Hanover, Germany
Partners AIDS Research Center, Harvard Medical School & Massachusetts General Hospital, Boston, MA, Germany
Department of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
Department of Medicine, Vanderbilt University Medical Center, Infectious Diseases Unit, Nashville, TN, USA
Department of Medicine, Vanderbilt University Medical Center, Infectious Diseases Unit, Nashville, TN, USA; Partners AIDS Research Center, Harvard Medical School & Massachusetts General Hospital, Boston, MA, Germany; Department of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
* Corresponding author; email: Spyros.a.kalams{at}vanderbilt.edu.
T cell receptor diversity of virus-specific CD8+ T cells likely helps prevent escape mutations in chronic viral infections. To understand the dynamics of the virus-specific T cells in more detail, we followed the evolution of the TCR repertoire specific for a dominant HLA-B*08-restricted epitope in Nef (FLKEKGGL) in a cohort of HIV infected subjects. Epitope-specific CD8+ T cells utilized structurally diverse TCR repertoires, with different TCR variable regions and with high amino acid diversity within antigen recognition sites. In a longitudinal study, distinct V-populations within the HIV-specific TCR repertoire expanded simultaneously with changes in plasma viremia, whereas other V-populations remained stable or even decreased. Despite antigenic variation in some subjects, all subjects had the consensus sequence present during the study period. Functional analysis of distinct V-populations revealed differences in HIV-specific IFN- secretion ex vivo as well as differences in tetramer binding, indicating functional heterogeneity among these populations. This contrasts findings in a subject on anti-retroviral therapy with suppression of viremia to <50 copies/ml, where we observed long-term persistence of a single clonotype. Our findings illustrate the flexibility of a heterogeneous HIV-1-specific CD8+ T cell receptor repertoire in subjects with partial control of viremia.
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