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Issy-les-Moulineaux, France

Puronen C.E.,National Institute of Allergy and Infectious Diseases | Puronen C.E.,University of Washington | Thompson W.L.,National Institute of Allergy and Infectious Diseases | Imamichi H.,National Institute of Allergy and Infectious Diseases | And 8 more authors.
Journal of Infectious Diseases | Year: 2012

Background. Elevated serum interleukin 7 (IL-7) levels are observed in lymphopenic conditions, including idiopathic CD4 lymphopenia (ICL), which is characterized by CD4 lymphopenia in the absence of human immunodeficiency virus infection or other known immunodeficiency. Methods. To test whether defective IL-7 signaling could be an etiologic or contributing factor in ICL, peripheral blood mononuclear cells from patients with ICL (median CD4 T-cell count, 160 cells/μL) and healthy controls (median CD4 T-cell count, 582 cells/μL) were evaluated for expression of IL-7Rα chain (CD127) and intracellular phosphorylated STAT-5 (a marker of γc cytokine signaling) after cytokine stimulation. Gene expression was analyzed by real-time polymerase chain reaction following IL-7 stimulation.Results.The percentage of CD4+CD127+ T cells was lower in patients with ICL, compared with controls (P <. 001). Lower levels of STAT-5 phosphorylation after IL-7 stimulation were observed in both CD4 and CD8 T cells from patients with ICL, compared with controls (P <. 001 and P =. 017, respectively), that inversely correlated in CD4 T cells with serum IL-7 levels (r =-0.734, P =. 013). Destabilization of p27 kip1, a critical step for IL-7-induced T-cell cycling, was decreased in patients with ICL, compared with controls (P =. 004), after IL-7 stimulation.Conclusions.These data suggest that diminished responsiveness to IL-7 in CD4 and CD8 T cells during ICL may be contributing to the dysregulation of T-cell homeostasis. © 2012 The Author.

Fabre-Mersseman V.,Institute Cochin | Fabre-Mersseman V.,French Institute of Health and Medical Research | Fabre-Mersseman V.,French National Center for Scientific Research | Fabre-Mersseman V.,University of Paris Descartes | And 20 more authors.
AIDS | Year: 2011

Objective: The contribution of naive CD4+T cells to the pool of HIV-infected cells remains poorly described. This study aimed at evaluating HIV infection in naive T-cell subsets in viremic and HAART-treated patients, together with various parameters implicated in naive T-cell homeostasis, in order to better understand infection in these subsets. DESIGN AND METHODS:: HIV provirus was quantified in various FACS-sorted CD4/CD8 T-cell subsets [recent thymic emigrants (RTEs), non-RTE naives and memory T cells] purified from peripheral blood cells of untreated viremic and HAART-treated aviremic HIV-infected patients. HIV proviral DNA was quantified using a highly sensitive real-time PCR assay allowing detection of one HIV copy in 10 cells. Intrathymic precursor T-cell proliferation and circulating T-cell cycling were, respectively, evaluated through measurement of the sj/βTREC ratio (signal joint T-Cell Receptor Excision Circle frequency divided by DβJβTREC frequency) and Ki-67 expression. Plasma interleukin (IL)-7 concentrations were measured by ELISA. Results: RTEs and non-RTEs were equally HIV infected. Altogether, naive CD4 T cells represented 0.24%-60% of the infected cells. In contrast, HIV DNA was undetectable in naive CD8 T cells. RTE infection rate directly correlated with IL-7 plasma levels (r = 0.607, P = 0.0035) but was independent from plasma viral load, peripheral T-cell cycling and intrathymic precursor T-cell proliferation. Conclusion: We demonstrated that RTEs are effectively HIV infected. The similar infection rate observed in RTEs and other naive T cells, its relationship with plasma IL-7 levels, together with the lack of correlation between RTE infection and either thymic or peripheral proliferation, strongly suggests that RTE infection occurs either late during thymopoiesis or early on during their extrathymic maturation. © 2011 Wolters Kluwer Health - Lippincott Williams & Wilkins.

Sospedra M.,University of Hamburg | Sospedra M.,University of Zurich | Schippling S.,University of Hamburg | Schippling S.,University of Zurich | And 13 more authors.
Clinical Infectious Diseases | Year: 2014

Progressive multifocal leukoencephalopathy is a currently untreatable infection of the brain. Here, we demonstrate in 2 patients that treatment with interleukin 7, JC polyomavirus (JCV) capsid protein VP1, and a Toll-like receptor 7 agonist used as adjuvant, was well tolerated, and showed a very favorable safety profile and unexpected efficacy that warrant further investigation. © The Author 2014.

Janot-Sardet C.,Cytheris SA | Assouline B.,Cytheris SA | Cheynier R.,Institute Pasteur Paris | Morre M.,Cytheris SA | Beq S.,Cytheris SA
Journal of Immunological Methods | Year: 2010

IL-7 is a crucial cytokine for T cell hematopoiesis and peripheral homeostasis which by signaling through its receptor alpha chain (CD127) is essential for inducing T cell proliferation and survival. Since the specific CD127 alpha chain is found in a soluble state (sCD127) and at a high level in plasma (ng/mL), it is important to develop a sensitive and reliable assay in order to investigate the potential role of this receptor in the regulation of IL-7 physiologic, physipathologic and therapeutic effects. We here report a fully validated method to measure sCD127 in human and simian plasma using a method based on ELISA MSD technology. We demonstrate that sCD127 is detectable at various levels in the plasma of healthy humans as well as in that of healthy Rhesus and Cynomolgus macaques (106.72, 205.26 and 366.95 ng/mL respectively). Moreover, as opposed to the sCD25/IL-2 tandem, we demonstrate that IL-7 treatment has no impact on sCD127 plasma concentration in patients infected by HIV. © 2009 Elsevier B.V.

Levy Y.,French Institute of Health and Medical Research | Levy Y.,University Paris Est Creteil | Sereti I.,National Institute of Allergy and Infectious Diseases | Tambussi G.,San Raffaele Scientific Institute | And 15 more authors.
Clinical Infectious Diseases | Year: 2012

Background. The immune deficiency of human immunodeficiency virus (HIV) infection is not fully corrected with ARV therapy. Interleukin-7 (IL-7) can boost CD4 T-cell counts, but optimal dosing and mechanisms of cellular increases need to be defined. Methods. We performed a randomized placebo-controlled dose escalation (10, 20 and 30 g/kg) trial of 3 weekly doses of recombinant human IL-7 (rhIL-7) in ARV-treated HIV-infected persons with CD4 T-cell counts between 101 and 400 cells/L and plasma HIV levels <50 copies/mL. Toxicity, activity and the impact of rhIL-7 on immune reconstitution were monitored.Results.Doses of rhIL-7 up to 20 g/kg were well tolerated. CD4 increases of predominantly naive and central memory T cells were brisk (averaging 323 cells/L at 12 weeks) and durable (up to 1 year). Increased cell cycling and transient increased bcl-2 expression were noted. Expanded cells did not have the characteristics of regulatory or activated T cells. Transient low-level HIV viremia was seen in 6 of 26 treated patients; modest increases in total levels of intracellular HIV DNA were proportional to CD4 T-cell expansions. IL-7 seemed to increase thymic output and tended to improve the T-cell receptor (TCR) repertoire in persons with low TCR diversity. Conclusions. Three weekly doses of rhIL-7 at 20 g/kg are well tolerated and lead to a dose-dependent CD4 T-cell increase and the broadening of TCR diversity in some subjects. These data suggest that this rhIL-7 dose could be advanced in future rhIL-7 clinical studies. Clinical Trials Registration NCT0047732. © 2012 The Author.

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