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

• Published in: PLoS pathogens 2016-04, Vol.12 (4), p.e1005571-e1005571
• Main Authors: Menkova-Garnier, Inna, Hocini, Hakim, Foucat, Emile, Tisserand, Pascaline, Bourdery, Laure, Delaugerre, Constance, Benne, Clarisse, Lévy, Yves, Lelièvre, Jean-Daniel
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; AIDS; Anti-Retroviral Agents - therapeutic use; Antigens, CD34 - metabolism; Antiretroviral drugs; Biology and Life Sciences; CD4 lymphocytes; Cell differentiation; Cell Differentiation - immunology; Development and progression; Drug Resistance, Viral - immunology; Flow Cytometry; Growth; Health aspects; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - immunology; HIV; HIV infections; HIV Infections - drug therapy; HIV Infections - immunology; HIV Infections - metabolism; Human immunodeficiency virus; Humans; Lentivirus; Lymphopoiesis - immunology; Medicine and Health Sciences; Oligonucleotide Array Sequence Analysis; Real-Time Polymerase Chain Reaction; Receptors, Purinergic P2X7 - immunology; Receptors, Purinergic P2X7 - metabolism; Studies; T-Lymphocytes - cytology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1005571

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.