title: P2X7 Receptor Inhibition Improves CD34 T-Cell Differentiation in HIV-Infected Immunological Nonresponders on c-ART.
abstract: 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.
authors.affiliation: INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France.|Université Paris Est Créteil, Faculté de Médecine, Créteil, France.|Vaccine Research Institute, Créteil, France.
authors.forename: Inna
authors.initials: I
authors.lastname: Menkova-Garnier
authors.affiliation: INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France.|Vaccine Research Institute, Créteil, France.
authors.forename: Hakim
authors.initials: H
authors.lastname: Hocini
authors.affiliation: Université Paris Est Créteil, Faculté de Médecine, Créteil, France.
authors.forename: Emile
authors.initials: E
authors.lastname: Foucat
authors.affiliation: INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France.|Vaccine Research Institute, Créteil, France.
authors.forename: Pascaline
authors.initials: P
authors.lastname: Tisserand
authors.affiliation: Université Paris Est Créteil, Faculté de Médecine, Créteil, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Bourdery
authors.affiliation: Laboratoire de Virologie Hôpital Saint-Louis, Paris, France.
authors.forename: Constance
authors.initials: C
authors.lastname: Delaugerre
authors.affiliation: INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France.|Université Paris Est Créteil, Faculté de Médecine, Créteil, France.
authors.forename: Clarisse
authors.initials: C
authors.lastname: Benne
authors.affiliation: INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France.|Université Paris Est Créteil, Faculté de Médecine, Créteil, France.|Vaccine Research Institute, Créteil, France.|Groupe Hospitalier Henri-Mondor Albert-Chenevier, Créteil, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Lévy
authors.affiliation: INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France.|Université Paris Est Créteil, Faculté de Médecine, Créteil, France.|Vaccine Research Institute, Créteil, France.|Groupe Hospitalier Henri-Mondor Albert-Chenevier, Créteil, France.
authors.forename: Jean-Daniel
authors.initials: JD
authors.lastname: Lelièvre
mesh_terms: D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D018952:Antigens, CD34 / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D024882:Drug Resistance, Viral / Q000276:immunology*; D005434:Flow Cytometry; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology*; D006801:Humans; D038041:Lymphopoiesis / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D058486:Receptors, Purinergic P2X7 / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism
chemical_list: D044966:Anti-Retroviral Agents; D018952:Antigens, CD34; D058486:Receptors, Purinergic P2X7