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Broad TCR Usage in Functional HIV-1-Specific CD8⁺ T Cell Expansions Driven by Vaccination during Highly Active Antiretroviral Therapy¹

Hongbing Yang^*, Tao Dong^*, Emma Turnbull, Srinika Ranasinghe^*, Beatrice Ondondo^*, Nilu Goonetilleke^*, Nicola Winstone^*, Kati di Gleria^*, Paul Bowness^*, Christopher Conlon, Persephone Borrow, Tomá Hanke^*, Andrew McMichael^* and Lucy Dorrell^2,*

^* Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, and Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, United Kingdom; and Edward Jenner Institute for Vaccine Research, Compton, Berkshire, United Kingdom

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 V 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 V 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was sponsored and funded by U.K. Medical Research Council. L.D. is the recipient of a U.K. Medical Research Council Clinician Scientist Fellowship.

² Address correspondence and reprint requests to Dr. Lucy Dorrell, Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, U.K. E-mail address: lucy.dorrell{at}imm.ox.ac.uk

³ Abbreviations used in this paper: HAART, highly active antiretroviral therapy; HDA, heteroduplex assay; PD-1, programmed death-1.

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