title: Broad TCR usage in functional HIV-1-specific CD8+ T cell expansions driven by vaccination during highly active antiretroviral therapy.
abstract: During chronic HIV-1 infection, continuing viral replication is associated with impaired proliferative capacity of virus-specific CD8+ T cells and with the expansion and persistence of oligoclonal T cell populations. TCR usage may significantly influence CD8+ T cell-mediated control of AIDS viruses; however, the potential to modulate the repertoire of functional virus-specific T cells by immunotherapy has not been explored. To investigate this, we analyzed the TCR Vbeta usage of CD8+ T cells populations which were expanded following vaccination with modified vaccinia virus Ankara expressing a HIV-1 gag/multiepitope immunogen (MVA.HIVA) in HIV-1-infected patients receiving highly active antiretroviral therapy. Vaccinations induced the re-expansion of HIV-1-specific CD8+ T cells and these showed broad TCR Vbeta usage which was maintained for at least 1 year in some individuals. By contrast, virus-specific CD8+ T cell populations in the same donors which failed to expand after vaccination and in unvaccinated controls were oligoclonal. Simultaneously, we observed that CD8+ T cells recognizing vaccine-derived HIV-1 epitopes displayed enhanced capacity to proliferate and to inhibit HIV-1 replication in vitro, following MVA.HIVA immunizations. Taken together, these data indicate that an attenuated viral-vectored vaccine can modulate adaptive CD8+ T cell responses to HIV-1 and improve their antiviral functional capacity. The potential therapeutic benefit of this vaccination approach warrants further investigation.
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Yang
authors.forename: Tao
authors.initials: T
authors.lastname: Dong
authors.forename: Emma
authors.initials: E
authors.lastname: Turnbull
authors.forename: Srinika
authors.initials: S
authors.lastname: Ranasinghe
authors.forename: Beatrice
authors.initials: B
authors.lastname: Ondondo
authors.forename: Nilu
authors.initials: N
authors.lastname: Goonetilleke
authors.forename: Nicola
authors.initials: N
authors.lastname: Winstone
authors.forename: Kati
authors.initials: K
authors.lastname: di Gleria
authors.forename: Paul
authors.initials: P
authors.lastname: Bowness
authors.forename: Christopher
authors.initials: C
authors.lastname: Conlon
authors.forename: Persephone
authors.initials: P
authors.lastname: Borrow
authors.forename: Tomás
authors.initials: T
authors.lastname: Hanke
authors.forename: Andrew
authors.initials: A
authors.lastname: McMichael
authors.forename: Lucy
authors.initials: L
authors.lastname: Dorrell
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D023241:Antiretroviral Therapy, Highly Active; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002908:Chronic Disease; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D015683:Gene Products, gag / Q000235:genetics / Q000276:immunology; D015693:Gene Products, nef / Q000235:genetics / Q000276:immunology; D015684:Gene Products, pol / Q000235:genetics / Q000276:immunology; D019674:Genes, T-Cell Receptor beta; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control; D015497:HIV-1 / Q000235:genetics / Q000254:growth & development / Q000276:immunology*; D006801:Humans; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis* / Q000235:genetics; D054311:nef Gene Products, Human Immunodeficiency Virus
chemical_list: D016915:AIDS Vaccines; D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D015693:Gene Products, nef; D015684:Gene Products, pol; D016693:Receptors, Antigen, T-Cell, alpha-beta; D054311:nef Gene Products, Human Immunodeficiency Virus