title: Fluctuations of functionally distinct CD8+ T-cell clonotypes demonstrate flexibility of the HIV-specific TCR repertoire.
abstract: 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 TCRbeta variable regions and with high amino acid diversity within antigen recognition sites. In a longitudinal study, distinct Vbeta populations within the HIV-specific TCR repertoire expanded simultaneously with changes in plasma viremia, whereas other Vbeta 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 Vbeta populations revealed differences in HIV-specific IFN-gamma 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.
authors.affiliation: Infectious Diseases Unit, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Dirk
authors.initials: D
authors.lastname: Meyer-Olson
authors.forename: Kristen W
authors.initials: KW
authors.lastname: Brady
authors.forename: Melissa T
authors.initials: MT
authors.lastname: Bartman
authors.forename: Kristin M
authors.initials: KM
authors.lastname: O'Sullivan
authors.forename: Brenna C
authors.initials: BC
authors.lastname: Simons
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Conrad
authors.forename: Coley B
authors.initials: CB
authors.lastname: Duncan
authors.forename: Shelly
authors.initials: S
authors.lastname: Lorey
authors.forename: Atif
authors.initials: A
authors.lastname: Siddique
authors.forename: Rika
authors.initials: R
authors.lastname: Draenert
authors.forename: Marylyn
authors.initials: M
authors.lastname: Addo
authors.forename: Marcus
authors.initials: M
authors.lastname: Altfeld
authors.forename: Eric
authors.initials: E
authors.lastname: Rosenberg
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Spyros A
authors.initials: SA
authors.lastname: Kalams
mesh_terms: D000328:Adult; D000368:Aged; D000940:Antigenic Variation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002999:Clone Cells / Q000276:immunology; D015331:Cohort Studies; D016384:Consensus Sequence; D006678:HIV / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes; D007371:Interferon-gamma / Q000378:metabolism; D008137:Longitudinal Studies; D008875:Middle Aged; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D037182:T-Cell Antigen Receptor Specificity; D014766:Viremia / Q000517:prevention & control
chemical_list: D016056:Immunodominant Epitopes; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma