P2X7 Receptor Inhibition Improves CD34 T-Cell Differentiation in HIV-Infected Immunological Nonresponders on c-ART

Peripheral CD4+ T-cell levels are not fully restored in a significant proportion of HIV+ individuals displaying long-term viral suppression on c-ART. These immunological nonresponders (INRs) have a higher risk of developing AIDS and non-AIDS events and a lower life expectancy than the general popula...

Descripción completa

Detalles Bibliográficos
Autores principales: Menkova-Garnier, Inna, Hocini, Hakim, Foucat, Emile, Tisserand, Pascaline, Bourdery, Laure, Delaugerre, Constance, Benne, Clarisse, Lévy, Yves, Lelièvre, Jean-Daniel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833302/
https://www.ncbi.nlm.nih.gov/pubmed/27082982
http://dx.doi.org/10.1371/journal.ppat.1005571
_version_ 1782427333455511552
author Menkova-Garnier, Inna
Hocini, Hakim
Foucat, Emile
Tisserand, Pascaline
Bourdery, Laure
Delaugerre, Constance
Benne, Clarisse
Lévy, Yves
Lelièvre, Jean-Daniel
author_facet Menkova-Garnier, Inna
Hocini, Hakim
Foucat, Emile
Tisserand, Pascaline
Bourdery, Laure
Delaugerre, Constance
Benne, Clarisse
Lévy, Yves
Lelièvre, Jean-Daniel
author_sort Menkova-Garnier, Inna
collection PubMed
description Peripheral CD4+ T-cell levels are not fully restored in a significant proportion of HIV+ individuals displaying long-term viral suppression on c-ART. These immunological nonresponders (INRs) have a higher risk of developing AIDS and non-AIDS events and a lower life expectancy than the general population, but the underlying mechanisms are not fully understood. We used an in vitro system to analyze the T- and B-cell potential of CD34+ hematopoietic progenitor cells. Comparisons of INRs with matched HIV+ patients with high CD4+ T-cell counts (immune responders (IRs)) revealed an impairment of the generation of T-cell progenitors, but not of B-cell progenitors, in INRs. This impairment resulted in the presence of smaller numbers of recent thymic emigrants (RTE) in the blood and lower peripheral CD4+ T-cell counts. We investigated the molecular pathways involved in lymphopoiesis, focusing particularly on T-cell fate specification (Notch pathway), survival (IL7R-IL7 axis) and death (Fas, P2X7, CD39/CD73). P2X7 expression was abnormally strong and there was no CD73 mRNA in the CD34+ cells of INRs, highlighting a role for the ATP pathway. This was confirmed by the demonstration that in vitro inhibition of the P2X7-mediated pathway restored the T-cell potential of CD34+ cells from INRs. Moreover, transcriptomic analysis revealed major differences in cell survival and death pathways between CD34+ cells from INRs and those from IRs. These findings pave the way for the use of complementary immunotherapies, such as P2X7 antagonists, to restore T-cell lymphopoiesis in INRs.
format Online
Article
Text
id pubmed-4833302
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-48333022016-04-22 P2X7 Receptor Inhibition Improves CD34 T-Cell Differentiation in HIV-Infected Immunological Nonresponders on c-ART Menkova-Garnier, Inna Hocini, Hakim Foucat, Emile Tisserand, Pascaline Bourdery, Laure Delaugerre, Constance Benne, Clarisse Lévy, Yves Lelièvre, Jean-Daniel PLoS Pathog Research Article Peripheral CD4+ T-cell levels are not fully restored in a significant proportion of HIV+ individuals displaying long-term viral suppression on c-ART. These immunological nonresponders (INRs) have a higher risk of developing AIDS and non-AIDS events and a lower life expectancy than the general population, but the underlying mechanisms are not fully understood. We used an in vitro system to analyze the T- and B-cell potential of CD34+ hematopoietic progenitor cells. Comparisons of INRs with matched HIV+ patients with high CD4+ T-cell counts (immune responders (IRs)) revealed an impairment of the generation of T-cell progenitors, but not of B-cell progenitors, in INRs. This impairment resulted in the presence of smaller numbers of recent thymic emigrants (RTE) in the blood and lower peripheral CD4+ T-cell counts. We investigated the molecular pathways involved in lymphopoiesis, focusing particularly on T-cell fate specification (Notch pathway), survival (IL7R-IL7 axis) and death (Fas, P2X7, CD39/CD73). P2X7 expression was abnormally strong and there was no CD73 mRNA in the CD34+ cells of INRs, highlighting a role for the ATP pathway. This was confirmed by the demonstration that in vitro inhibition of the P2X7-mediated pathway restored the T-cell potential of CD34+ cells from INRs. Moreover, transcriptomic analysis revealed major differences in cell survival and death pathways between CD34+ cells from INRs and those from IRs. These findings pave the way for the use of complementary immunotherapies, such as P2X7 antagonists, to restore T-cell lymphopoiesis in INRs. Public Library of Science 2016-04-15 /pmc/articles/PMC4833302/ /pubmed/27082982 http://dx.doi.org/10.1371/journal.ppat.1005571 Text en © 2016 Menkova-Garnier 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
Menkova-Garnier, Inna
Hocini, Hakim
Foucat, Emile
Tisserand, Pascaline
Bourdery, Laure
Delaugerre, Constance
Benne, Clarisse
Lévy, Yves
Lelièvre, Jean-Daniel
P2X7 Receptor Inhibition Improves CD34 T-Cell Differentiation in HIV-Infected Immunological Nonresponders on c-ART
title P2X7 Receptor Inhibition Improves CD34 T-Cell Differentiation in HIV-Infected Immunological Nonresponders on c-ART
title_full P2X7 Receptor Inhibition Improves CD34 T-Cell Differentiation in HIV-Infected Immunological Nonresponders on c-ART
title_fullStr P2X7 Receptor Inhibition Improves CD34 T-Cell Differentiation in HIV-Infected Immunological Nonresponders on c-ART
title_full_unstemmed P2X7 Receptor Inhibition Improves CD34 T-Cell Differentiation in HIV-Infected Immunological Nonresponders on c-ART
title_short P2X7 Receptor Inhibition Improves CD34 T-Cell Differentiation in HIV-Infected Immunological Nonresponders on c-ART
title_sort p2x7 receptor inhibition improves cd34 t-cell differentiation in hiv-infected immunological nonresponders on c-art
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833302/
https://www.ncbi.nlm.nih.gov/pubmed/27082982
http://dx.doi.org/10.1371/journal.ppat.1005571
work_keys_str_mv AT menkovagarnierinna p2x7receptorinhibitionimprovescd34tcelldifferentiationinhivinfectedimmunologicalnonrespondersoncart
AT hocinihakim p2x7receptorinhibitionimprovescd34tcelldifferentiationinhivinfectedimmunologicalnonrespondersoncart
AT foucatemile p2x7receptorinhibitionimprovescd34tcelldifferentiationinhivinfectedimmunologicalnonrespondersoncart
AT tisserandpascaline p2x7receptorinhibitionimprovescd34tcelldifferentiationinhivinfectedimmunologicalnonrespondersoncart
AT bourderylaure p2x7receptorinhibitionimprovescd34tcelldifferentiationinhivinfectedimmunologicalnonrespondersoncart
AT delaugerreconstance p2x7receptorinhibitionimprovescd34tcelldifferentiationinhivinfectedimmunologicalnonrespondersoncart
AT benneclarisse p2x7receptorinhibitionimprovescd34tcelldifferentiationinhivinfectedimmunologicalnonrespondersoncart
AT levyyves p2x7receptorinhibitionimprovescd34tcelldifferentiationinhivinfectedimmunologicalnonrespondersoncart
AT lelievrejeandaniel p2x7receptorinhibitionimprovescd34tcelldifferentiationinhivinfectedimmunologicalnonrespondersoncart