title: Antiretroviral therapy reduces the magnitude and T cell receptor repertoire diversity of HIV-specific T cell responses without changing T cell clonotype dominance.
abstract: After initiation of antiretroviral therapy (ART), HIV loads and frequencies of HIV epitope-specific immune responses decrease. A diverse virus-specific T cell receptor (TCR) repertoire allows the host to respond to viral epitope diversity, but the effect of antigen reduction as a result of ART on the TCR repertoire of epitope-specific CD8(+) T cell populations has not been well defined. We determined the TCR repertoires of 14 HIV-specific CD8(+) T cell responses from 8 HIV-positive individuals before and after initiation of ART. We used multiparameter flow cytometry to measure the distribution of memory T cell subsets and the surface expression of PD-1 on T cell populations and T cell clonotypes within epitope-specific responses from these individuals. Post-ART, we noted decreases in the frequency of circulating epitope-specific T cells (P = 0.02), decreases in the number of T-cell clonotypes found within epitope-specific T cell receptor repertoires (P = 0.024), and an overall reduction in the amino acid diversity within these responses (P < 0.0001). Despite this narrowing of the T cell response to HIV, the overall hierarchy of dominant T cell receptor clonotypes remained stable compared to that pre-ART. CD8(+) T cells underwent redistributions in memory phenotypes and a reduction in CD38 and PD-1 expression post-ART. Despite extensive remodeling at the structural and phenotypic levels, PD-1 was expressed at higher levels on dominant clonotypes within epitope-specific responses before and after initiation of ART. These data suggest that the antigen burden may maintain TCR diversity and that dominant clonotypes are sensitive to antigen even after dramatic reductions after initiation of ART.
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Conrad
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramalingam
authors.forename: Coley B
authors.initials: CB
authors.lastname: Duncan
authors.forename: Rita M
authors.initials: RM
authors.lastname: Smith
authors.forename: Jie
authors.initials: J
authors.lastname: Wei
authors.forename: Louise
authors.initials: L
authors.lastname: Barnett
authors.forename: Brenna C
authors.initials: BC
authors.lastname: Simons
authors.forename: Shelly L
authors.initials: SL
authors.lastname: Lorey
authors.forename: Spyros A
authors.initials: SA
authors.lastname: Kalams
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D014644:Genetic Variation / Q000187:drug effects / Q000276:immunology; D006678:HIV / Q000276:immunology*; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D007156:Immunologic Memory; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D019380:Anti-HIV Agents; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell