Effective Cytotoxic T Lymphocyte Targeting of Persistent HIV-1 during Antiretroviral Therapy Requires Priming of Naive CD8+ T Cells.

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

doi:10.1128/mbio.00473-16

Kellie N Smith, Bette T Korber + Show 8 more

Open Access

https://doi.org/10.1128/mbio.00473-16

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Abstract

ABSTRACTCuring 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 reservoir-associated 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.

Highlights

Combination antiretroviral therapy has greatly reduced the morbidity and mortality associated with chronic HIV-1 infection
The dendritic cells (DC)-stimulated memory cytotoxic T lymphocyte (CTL) antiviral function was indistinguishable from that observed in ex vivo CD8ϩ T cells, showing that CTL effector function was not enhanced by either short- or long-term DC stimulation of memory T cells. These findings demonstrate that naive CD8ϩ T cells in participants on Combination antiretroviral therapy (cART) can be primed by DC to recognize virus from reactivated autologous HIV-1, whereas memory CD8ϩ T cells exposed to this same stimulation have limited effector function and fail to effectively target these CD4ϩ T cells
We propose that immunotherapies can be designed to maximize the afferent arm of DC priming of naive CD8ϩ T cells through selective programming of the DC pathway and presentation of the patient’s autologous viral reservoir, thereby maximizing the efferent arm of CTL-mediated killing

Summary

Introduction

Combination antiretroviral therapy (cART) has greatly reduced the morbidity and mortality associated with chronic HIV-1 infection. “shock and kill” approach has been proposed In this concept, cells harboring the latent HIV-1 reservoir are induced to produce viral protein antigens (“shock”), coincident with a potent immunotherapy that induces CTL specific for the patient’s autologous virus (“kill”) [18]. Cells harboring the latent HIV-1 reservoir are induced to produce viral protein antigens (“shock”), coincident with a potent immunotherapy that induces CTL specific for the patient’s autologous virus (“kill”) [18] Such immunotherapies aim to reactivate HIV-1specific memory CD8ϩ T cells in persons on cART. We have previously shown that mature, antigen-loaded DC producing high levels of interleukin 12p70 (IL-12p70) can induce primary HIV-1-specific CD8ϩ T cells in HIV-1-naive donors [24, 26] It is currently unclear, whether the repertoire and function of naive T cells in HIV1-infected persons on cART are sufficient to enable a response to such a therapy. Our findings support the selective priming of naive CD8ϩ T cells in HIV-1-infected persons on cART using a DC-based therapeutic strategy to target the autologous HIV-1 reservoir

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