Effective cytotoxic T lymphocyte targeting of persistent HIV-1 during antiretroviral therapy requires priming of naive CD8+ T cells

Kellie Smith, Robbie B. Mailliard, Paolo A. Piazza, Will Fischer, Bette T. Korber, Ronald J. Fecek, Deena Ratner, Phalguni Gupta, James I. Mullins, Charles R. Rinaldob

Research output: Contribution to journalArticle

Abstract

Curing HIV-1 infection will require elimination of persistent cellular reservoirs that harbor latent virus in the face of combination antiretroviral therapy (cART). Proposed immunotherapeutic strategies to cure HIV-1 infection include enhancing lysis of these infected cells by cytotoxic T lymphocytes (CTL). A major challenge in this strategy is overcoming viral immune escape variants that have evaded host immune control. Here we report that naive CD8+ T cells from chronic HIV-1-infected participants on long-term cART can be primed by dendritic cells (DC). These DC must be mature, produce high levels of interleukin 12p70 (IL-12p70), be responsive to CD40 ligand (CD40L), and be loaded with inactivated, autologous HIV-1. These DC-primed CD8+ T cell responders produced high levels of gamma interferon (IFN-γ) in response to a broad range of both conserved and variable regions of Gag and effectively killed CD4+ T cell targets that were either infected with the autologous latent reservoirassociated virus or loaded with autologous Gag peptides. In contrast, HIV-1-specific memory CD8+ T cells stimulated with autologous HIV-1-loaded DC produced IFN-γ in response to a narrow range of conserved and variable Gag peptides compared to the primed T cells and most notably, displayed significantly lower cytolytic function. Our findings highlight the need to selectively induce new HIV-1-specific CTL from naive precursors while avoiding activation of existing, dysfunctional memory T cells in potential curative immunotherapeutic strategies for HIV-1 infection. IMPORTANCE Current immunotherapeutic approaches aim to enhance antiviral immunity against the HIV-1 reservoir; however, it has yet to be shown whether T cells from persons on cART can recognize and eliminate virus-infected cells. We show that in persons on cART a personalized medicine approach using their dendritic cells to stimulate their naive T cells induces potent effector CTL in vitro that recognize and eradicate HIV-1-infected CD4+ T cells. Additionally, we show that the same stimulation of existing memory T cells results in cytokine secretion but limited effector function. Our study demonstrates that the naive T cell repertoire can recognize persistent HIV-1 during cART and supports immunotherapy strategies for an HIV-1 cure that targets naive T cells, rather than existing, dysfunctional, memory T cells.

Original languageEnglish (US)
Article numbere00473-16
JournalmBio
Volume7
Issue number3
DOIs
StatePublished - 2016

ASJC Scopus subject areas

  • Microbiology
  • Virology

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    Smith, K., Mailliard, R. B., Piazza, P. A., Fischer, W., Korber, B. T., Fecek, R. J., Ratner, D., Gupta, P., Mullins, J. I., & Rinaldob, C. R. (2016). Effective cytotoxic T lymphocyte targeting of persistent HIV-1 during antiretroviral therapy requires priming of naive CD8+ T cells. mBio, 7(3), [e00473-16]. https://doi.org/10.1128/mBio.00473-16