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 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. © 2016 menkova-garnier et al.