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Regulatory B Cells Inhibit Cytotoxic T Lymphocyte (CTL) Activity and Elimination of Infected CD4 T Cells after In Vitro Reactivation of HIV Latent Reservoirs

During HIV infection, IL-10/IL-10 receptor and programmed death-1 (PD-1)/programmed death-1-ligand (PD-L1) interactions have been implicated in the impairment of cytotoxic T lymphocyte (CTL) activity. Despite antiretroviral therapy (ART), attenuated anti-HIV CTL functions present a major hurdle towa...

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Autores principales: Siewe, Basile, Wallace, Jennillee, Rygielski, Sonya, Stapleton, Jack T., Martin, Jeffrey, Deeks, Steven G., Landay, Alan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3989168/
https://www.ncbi.nlm.nih.gov/pubmed/24739950
http://dx.doi.org/10.1371/journal.pone.0092934
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author Siewe, Basile
Wallace, Jennillee
Rygielski, Sonya
Stapleton, Jack T.
Martin, Jeffrey
Deeks, Steven G.
Landay, Alan
author_facet Siewe, Basile
Wallace, Jennillee
Rygielski, Sonya
Stapleton, Jack T.
Martin, Jeffrey
Deeks, Steven G.
Landay, Alan
author_sort Siewe, Basile
collection PubMed
description During HIV infection, IL-10/IL-10 receptor and programmed death-1 (PD-1)/programmed death-1-ligand (PD-L1) interactions have been implicated in the impairment of cytotoxic T lymphocyte (CTL) activity. Despite antiretroviral therapy (ART), attenuated anti-HIV CTL functions present a major hurdle towards curative measures requiring viral eradication. Therefore, deeper understanding of the mechanisms underlying impaired CTL is crucial before HIV viral eradication is viable. The generation of robust CTL activity necessitates interactions between antigen-presenting cells (APC), CD4(+) and CD8(+) T cells. We have shown that in vitro, IL-10(hi)PD-L1(hi) regulatory B cells (Bregs) directly attenuate HIV-specific CD8(+)-mediated CTL activity. Bregs also modulate APC and CD4(+) T cell function; herein we characterize the Breg compartment in uninfected (HIV(NEG)), HIV-infected “elite controllers” (HIV(EC)), ART-treated (HIV(ART)), and viremic (HIV(vir)), subjects, and in vitro, assess the impact of Bregs on anti-HIV CTL generation and activity after reactivation of HIV latent reservoirs using suberoylanilide hydroxamic acid (SAHA). We find that Bregs from HIV(EC) and HIV(ART) subjects exhibit comparable IL-10 expression levels significantly higher than HIV(NEG) subjects, but significantly lower than HIV(VIR) subjects. Bregs from HIV(EC) and HIV(ART) subjects exhibit comparable PD-L1 expression, significantly higher than in HIV(VIR) and HIV(NEG) subjects. SAHA-treated Breg-depleted PBMC from HIV(EC) and HIV(ART) subjects, displayed enhanced CD4(+) T-cell proliferation, significant upregulation of antigen-presentation molecules, increased frequency of CD107a(+) and HIV-specific CD8(+) T cells, associated with efficient elimination of infected CD4(+) T cells, and reduction in integrated viral DNA. Finally, IL-10-R and PD-1 antibody blockade partially reversed Breg-mediated inhibition of CD4(+) T-cell proliferation. Our data suggest that, possibly, via an IL-10 and PD-L1 synergistic mechanism; Bregs likely inhibit APC function and CD4(+) T-cell proliferation, leading to anti-HIV CTL attenuation, hindering viral eradication.
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spelling pubmed-39891682014-04-21 Regulatory B Cells Inhibit Cytotoxic T Lymphocyte (CTL) Activity and Elimination of Infected CD4 T Cells after In Vitro Reactivation of HIV Latent Reservoirs Siewe, Basile Wallace, Jennillee Rygielski, Sonya Stapleton, Jack T. Martin, Jeffrey Deeks, Steven G. Landay, Alan PLoS One Research Article During HIV infection, IL-10/IL-10 receptor and programmed death-1 (PD-1)/programmed death-1-ligand (PD-L1) interactions have been implicated in the impairment of cytotoxic T lymphocyte (CTL) activity. Despite antiretroviral therapy (ART), attenuated anti-HIV CTL functions present a major hurdle towards curative measures requiring viral eradication. Therefore, deeper understanding of the mechanisms underlying impaired CTL is crucial before HIV viral eradication is viable. The generation of robust CTL activity necessitates interactions between antigen-presenting cells (APC), CD4(+) and CD8(+) T cells. We have shown that in vitro, IL-10(hi)PD-L1(hi) regulatory B cells (Bregs) directly attenuate HIV-specific CD8(+)-mediated CTL activity. Bregs also modulate APC and CD4(+) T cell function; herein we characterize the Breg compartment in uninfected (HIV(NEG)), HIV-infected “elite controllers” (HIV(EC)), ART-treated (HIV(ART)), and viremic (HIV(vir)), subjects, and in vitro, assess the impact of Bregs on anti-HIV CTL generation and activity after reactivation of HIV latent reservoirs using suberoylanilide hydroxamic acid (SAHA). We find that Bregs from HIV(EC) and HIV(ART) subjects exhibit comparable IL-10 expression levels significantly higher than HIV(NEG) subjects, but significantly lower than HIV(VIR) subjects. Bregs from HIV(EC) and HIV(ART) subjects exhibit comparable PD-L1 expression, significantly higher than in HIV(VIR) and HIV(NEG) subjects. SAHA-treated Breg-depleted PBMC from HIV(EC) and HIV(ART) subjects, displayed enhanced CD4(+) T-cell proliferation, significant upregulation of antigen-presentation molecules, increased frequency of CD107a(+) and HIV-specific CD8(+) T cells, associated with efficient elimination of infected CD4(+) T cells, and reduction in integrated viral DNA. Finally, IL-10-R and PD-1 antibody blockade partially reversed Breg-mediated inhibition of CD4(+) T-cell proliferation. Our data suggest that, possibly, via an IL-10 and PD-L1 synergistic mechanism; Bregs likely inhibit APC function and CD4(+) T-cell proliferation, leading to anti-HIV CTL attenuation, hindering viral eradication. Public Library of Science 2014-04-16 /pmc/articles/PMC3989168/ /pubmed/24739950 http://dx.doi.org/10.1371/journal.pone.0092934 Text en © 2014 Siewe et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Siewe, Basile
Wallace, Jennillee
Rygielski, Sonya
Stapleton, Jack T.
Martin, Jeffrey
Deeks, Steven G.
Landay, Alan
Regulatory B Cells Inhibit Cytotoxic T Lymphocyte (CTL) Activity and Elimination of Infected CD4 T Cells after In Vitro Reactivation of HIV Latent Reservoirs
title Regulatory B Cells Inhibit Cytotoxic T Lymphocyte (CTL) Activity and Elimination of Infected CD4 T Cells after In Vitro Reactivation of HIV Latent Reservoirs
title_full Regulatory B Cells Inhibit Cytotoxic T Lymphocyte (CTL) Activity and Elimination of Infected CD4 T Cells after In Vitro Reactivation of HIV Latent Reservoirs
title_fullStr Regulatory B Cells Inhibit Cytotoxic T Lymphocyte (CTL) Activity and Elimination of Infected CD4 T Cells after In Vitro Reactivation of HIV Latent Reservoirs
title_full_unstemmed Regulatory B Cells Inhibit Cytotoxic T Lymphocyte (CTL) Activity and Elimination of Infected CD4 T Cells after In Vitro Reactivation of HIV Latent Reservoirs
title_short Regulatory B Cells Inhibit Cytotoxic T Lymphocyte (CTL) Activity and Elimination of Infected CD4 T Cells after In Vitro Reactivation of HIV Latent Reservoirs
title_sort regulatory b cells inhibit cytotoxic t lymphocyte (ctl) activity and elimination of infected cd4 t cells after in vitro reactivation of hiv latent reservoirs
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3989168/
https://www.ncbi.nlm.nih.gov/pubmed/24739950
http://dx.doi.org/10.1371/journal.pone.0092934
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