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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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IMMUNOBIOLOGY
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 Draenert,
Marylyn Addo,
Marcus Altfeld,
Eric Rosenberg,
Todd M. Allen,
Bruce D. Walker, and
Spyros A. Kalams
From the Infectious Diseases Unit, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN; the Partners AIDS Research Center, Harvard Medical School and Massachusetts General Hospital, Boston, MA; the Abteilung Klinische Immunologie, Medizinische Hochschule Hannover, Hanover, Germany; and the Department of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN.
T-cell receptor (TCR) 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 subjects infected with HIV. Epitope-specific CD8+ T cells used 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 with findings in a subject on antiretroviral therapy with suppression of viremia to less than 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+ TCR repertoire in subjects with partial control of viremia.
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