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Type 1-programmed dendritic cells drive antigen-specific latency reversal and immune elimination of persistent HIV-1
BACKGROUND: Despite the success of antiretroviral therapy (ART), latent HIV-1 continues to persist in a long-lived population of resting memory CD4(+) T cells within those who are infected. Finding a safe and effective means to induce latency reversal (LR) during ART to specifically expose this late...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557749/ https://www.ncbi.nlm.nih.gov/pubmed/30952614 http://dx.doi.org/10.1016/j.ebiom.2019.03.077 |
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author | Kristoff, Jan Palma, Mariana L. Garcia-Bates, Tatiana M. Shen, Chengli Sluis-Cremer, Nicolas Gupta, Phalguni Rinaldo, Charles R. Mailliard, Robbie B. |
author_facet | Kristoff, Jan Palma, Mariana L. Garcia-Bates, Tatiana M. Shen, Chengli Sluis-Cremer, Nicolas Gupta, Phalguni Rinaldo, Charles R. Mailliard, Robbie B. |
author_sort | Kristoff, Jan |
collection | PubMed |
description | BACKGROUND: Despite the success of antiretroviral therapy (ART), latent HIV-1 continues to persist in a long-lived population of resting memory CD4(+) T cells within those who are infected. Finding a safe and effective means to induce latency reversal (LR) during ART to specifically expose this latent HIV-1 cellular reservoir for immune elimination has been a major barrier to a functional cure. METHODS: In this study, we test the use of antigen-presenting type 1-polarized, monocyte-derived dendritic cells (MDC1) generated from chronic HIV-1-infected individuals on ART as a means to induce HIV-1 latency reversal in autologous CD4(+) T cells harboring replication-competent provirus. We use the same MDC1 for ex-vivo generation of autologous HIV-1 antigen-specific CD8(+) cytotoxic T cells (CTL) and test their effector responses against the MDC1-exposed HIV-1- infected CD4(+) T cell targets. FINDINGS: MDC1 presentation of either HIV-1 or cytomegalovirus (CMV) antigens to CD4(+) T cells facilitated HIV-1 LR. This antigen-driven MDC1-mediated LR was sharply diminished with blockade of the CD40L/CD40 ‘helper’ signaling pathway. Importantly, these antigen-presenting MDC1 also activated the expansion of CTL capable of killing the exposed HIV-1-infected targets. INTERPRETATION: Inclusion of virus-associated MHC class II ‘helper’ antigens in MDC1-based HIV-1 immunotherapies could serve both as a targeted means to safely unmask antigen-specific CD4(+) T cells harboring HIV-1, and to support CTL responses that can effectively target the MDC1-exposed HIV-1 cellular reservoir as a functional cure strategy. FUND: This study was supported by the NIH-NAID grants R21-AI131763, U01-AI35041, UM1-AI126603, and T32-AI065380. |
format | Online Article Text |
id | pubmed-6557749 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-65577492019-06-13 Type 1-programmed dendritic cells drive antigen-specific latency reversal and immune elimination of persistent HIV-1 Kristoff, Jan Palma, Mariana L. Garcia-Bates, Tatiana M. Shen, Chengli Sluis-Cremer, Nicolas Gupta, Phalguni Rinaldo, Charles R. Mailliard, Robbie B. EBioMedicine Research paper BACKGROUND: Despite the success of antiretroviral therapy (ART), latent HIV-1 continues to persist in a long-lived population of resting memory CD4(+) T cells within those who are infected. Finding a safe and effective means to induce latency reversal (LR) during ART to specifically expose this latent HIV-1 cellular reservoir for immune elimination has been a major barrier to a functional cure. METHODS: In this study, we test the use of antigen-presenting type 1-polarized, monocyte-derived dendritic cells (MDC1) generated from chronic HIV-1-infected individuals on ART as a means to induce HIV-1 latency reversal in autologous CD4(+) T cells harboring replication-competent provirus. We use the same MDC1 for ex-vivo generation of autologous HIV-1 antigen-specific CD8(+) cytotoxic T cells (CTL) and test their effector responses against the MDC1-exposed HIV-1- infected CD4(+) T cell targets. FINDINGS: MDC1 presentation of either HIV-1 or cytomegalovirus (CMV) antigens to CD4(+) T cells facilitated HIV-1 LR. This antigen-driven MDC1-mediated LR was sharply diminished with blockade of the CD40L/CD40 ‘helper’ signaling pathway. Importantly, these antigen-presenting MDC1 also activated the expansion of CTL capable of killing the exposed HIV-1-infected targets. INTERPRETATION: Inclusion of virus-associated MHC class II ‘helper’ antigens in MDC1-based HIV-1 immunotherapies could serve both as a targeted means to safely unmask antigen-specific CD4(+) T cells harboring HIV-1, and to support CTL responses that can effectively target the MDC1-exposed HIV-1 cellular reservoir as a functional cure strategy. FUND: This study was supported by the NIH-NAID grants R21-AI131763, U01-AI35041, UM1-AI126603, and T32-AI065380. Elsevier 2019-04-02 /pmc/articles/PMC6557749/ /pubmed/30952614 http://dx.doi.org/10.1016/j.ebiom.2019.03.077 Text en © 2019 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research paper Kristoff, Jan Palma, Mariana L. Garcia-Bates, Tatiana M. Shen, Chengli Sluis-Cremer, Nicolas Gupta, Phalguni Rinaldo, Charles R. Mailliard, Robbie B. Type 1-programmed dendritic cells drive antigen-specific latency reversal and immune elimination of persistent HIV-1 |
title | Type 1-programmed dendritic cells drive antigen-specific latency reversal and immune elimination of persistent HIV-1 |
title_full | Type 1-programmed dendritic cells drive antigen-specific latency reversal and immune elimination of persistent HIV-1 |
title_fullStr | Type 1-programmed dendritic cells drive antigen-specific latency reversal and immune elimination of persistent HIV-1 |
title_full_unstemmed | Type 1-programmed dendritic cells drive antigen-specific latency reversal and immune elimination of persistent HIV-1 |
title_short | Type 1-programmed dendritic cells drive antigen-specific latency reversal and immune elimination of persistent HIV-1 |
title_sort | type 1-programmed dendritic cells drive antigen-specific latency reversal and immune elimination of persistent hiv-1 |
topic | Research paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557749/ https://www.ncbi.nlm.nih.gov/pubmed/30952614 http://dx.doi.org/10.1016/j.ebiom.2019.03.077 |
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