Effective Cytotoxic T Lymphocyte Targeting of Persistent HIV-1 during Antiretroviral Therapy Requires Priming of Naive CD8+ T Cells
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 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 themore »
- Authors:
-
- Univ. of Pittsburgh, PA (United States). Dept. of Microbiology and Molecular Genetics; Univ. of Pittsburgh, PA (United States). Dept. of Infectious Diseases and Microbiology
- Univ. of Pittsburgh, PA (United States). Dept. of Infectious Diseases and Microbiology
- Los Alamos National Lab. (LANL), Los Alamos, NM (United States). theoretical Biology and Biophysics Group
- Univ. of Washington, Seattle, WA (United States). Dept. of Microbiology
- Univ. of Pittsburgh, PA (United States). Dept. of Infectious Diseases and Microbiology; Univ. of Pittsburgh School of Medicine, PA (United States). Dept. of Pathology
- Publication Date:
- Research Org.:
- Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC)
- OSTI Identifier:
- 1626106
- Grant/Contract Number:
- AC52-06NA25396
- Resource Type:
- Accepted Manuscript
- Journal Name:
- mBio (Online)
- Additional Journal Information:
- Journal Name: mBio (Online); Journal Volume: 7; Journal Issue: 3; Journal ID: ISSN 2150-7511
- Publisher:
- American Society for Microbiology (ASM)
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Microbiology
Citation Formats
Smith, Kellie N., Mailliard, Robbie B., Piazza, Paolo A., Fischer, Will, Korber, Bette T., Fecek, Ronald J., Ratner, Deena, Gupta, Phalguni, Mullins, James I., and Rinaldo, Charles R. Effective Cytotoxic T Lymphocyte Targeting of Persistent HIV-1 during Antiretroviral Therapy Requires Priming of Naive CD8+ T Cells. United States: N. p., 2016.
Web. doi:10.1128/mbio.00473-16.
Smith, Kellie N., Mailliard, Robbie B., Piazza, Paolo A., Fischer, Will, Korber, Bette T., Fecek, Ronald J., Ratner, Deena, Gupta, Phalguni, Mullins, James I., & Rinaldo, Charles R. Effective Cytotoxic T Lymphocyte Targeting of Persistent HIV-1 during Antiretroviral Therapy Requires Priming of Naive CD8+ T Cells. United States. https://doi.org/10.1128/mbio.00473-16
Smith, Kellie N., Mailliard, Robbie B., Piazza, Paolo A., Fischer, Will, Korber, Bette T., Fecek, Ronald J., Ratner, Deena, Gupta, Phalguni, Mullins, James I., and Rinaldo, Charles R. Tue .
"Effective Cytotoxic T Lymphocyte Targeting of Persistent HIV-1 during Antiretroviral Therapy Requires Priming of Naive CD8+ T Cells". United States. https://doi.org/10.1128/mbio.00473-16. https://www.osti.gov/servlets/purl/1626106.
@article{osti_1626106,
title = {Effective Cytotoxic T Lymphocyte Targeting of Persistent HIV-1 during Antiretroviral Therapy Requires Priming of Naive CD8+ T Cells},
author = {Smith, Kellie N. and Mailliard, Robbie B. and Piazza, Paolo A. and Fischer, Will and Korber, Bette T. and Fecek, Ronald J. and Ratner, Deena and Gupta, Phalguni and Mullins, James I. and Rinaldo, Charles R.},
abstractNote = {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 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.},
doi = {10.1128/mbio.00473-16},
journal = {mBio (Online)},
number = 3,
volume = 7,
place = {United States},
year = {Tue May 31 00:00:00 EDT 2016},
month = {Tue May 31 00:00:00 EDT 2016}
}
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Works referencing / citing this record:
Role of Dendritic Cells in Exposing Latent HIV-1 for the Kill
journal, December 2019
- Kristoff, Jan; Rinaldo, Charles R.; Mailliard, Robbie B.
- Viruses, Vol. 12, Issue 1
CD8 T cells targeting adapted epitopes in chronic HIV infection promote dendritic cell maturation and CD4 T cell trans-infection
journal, August 2019
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- PLOS Pathogens, Vol. 15, Issue 8
Role of Dendritic Cells in Exposing Latent HIV-1 for the Kill
journal, December 2019
- Kristoff, Jan; Rinaldo, Charles R.; Mailliard, Robbie B.
- Viruses, Vol. 12, Issue 1
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