title: Despite an impaired response to IL-7, CD4+EM T cells from HIV-positive patients proliferate normally in response to IL-15 and its superagonist, RLI.
abstract: OBJECTIVE
  In phase I/II trials, IL-7 immunotherapy has been shown to expand CD4(+) T cells. However, expression of the IL-7 receptor α-chain, CD127, is reduced on CD4(+) T cells from HIV-positive patients, and defects in CD127 signaling have also been reported. To refine and improve cytokine immunotherapy, it is important to identify stimuli that can restore proliferation of CD4(+) cells with defective responses to IL-7.
  
  
  METHODS
  Observational study comparing viremic HIV-positive patients with HIV-negative controls.
  
  
  METHODS
  Peripheral blood mononuclear cells were cultured in the presence of 1 nmol/l IL-2, IL-7, IL-15 or RLI (an IL-15Rα/IL-15 fusion protein). Proliferation of different T-cell subsets was assessed by carboxyfluorescein succinimidyl ester fluorescence. Expression of CD127 on CD4(+) T-cell subsets was also analyzed.
  
  
  RESULTS
  In HIV-positive patients, CD127 expression was correlated with CD4(+) T-cell count in the CD4(+)(N) (R(2) = 0.36; P < 0.01) and CD4(+)(CM) (R(2) = 0.45; P < 0.001) populations, whereas CD127 expression on CD4(+)(EM) cells was significantly reduced in HIV-positive individuals compared with controls (P = 0.001) independently of CD4(+) T-cell count. In patients with high CD4(+) T-cell counts, proliferation in response to IL-7 was significantly reduced only in CD4(+)(EM) cells (P < 0.05). RLI, and to a lesser extent IL-15, induced strong proliferation of CD4(+)(EM) cells from both HIV-positive patients and controls. Neither agent stimulated proliferation of CD4(+)(N) or CD4(+)(CM) cells.
  
  
  CONCLUSIONS
  In HIV-positive patients, CD4(+)(EM) cells are deficient in both CD127 expression and proliferation in response to IL-7. RLI and IL-15 specifically induced proliferation of CD4(+)(EM) cells, suggesting that they may have a unique potential to complement IL-7 immunotherapy.
authors.affiliation: EA Laboratoire d'Immunovirologie et Polymorphisme Génétique, Université de Nantes, France.
authors.forename: Yovana
authors.initials: Y
authors.lastname: Pacheco
authors.forename: Véronique
authors.initials: V
authors.lastname: Solé
authors.forename: Eric
authors.initials: E
authors.lastname: Billaud
authors.forename: Clotilde
authors.initials: C
authors.lastname: Allavena
authors.forename: Ariane
authors.initials: A
authors.lastname: Plet
authors.forename: Virginie
authors.initials: V
authors.lastname: Ferré
authors.forename: Laure
authors.initials: L
authors.lastname: Garrigue-Antar
authors.forename: François
authors.initials: F
authors.lastname: Raffi
authors.forename: Yannick
authors.initials: Y
authors.lastname: Jacques
authors.forename: Dorian
authors.initials: D
authors.lastname: McIlroy
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D006801:Humans; D019409:Interleukin-15 / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D053647:Receptors, Interleukin-15 / Q000819:agonists* / Q000235:genetics / Q000276:immunology*; D020395:Receptors, Interleukin-7 / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology*
chemical_list: D019380:Anti-HIV Agents; C568159:IL-15Ralpha-sushi domain-linker-IL-15 fusion protein; C508024:IL15RA protein, human; D019409:Interleukin-15; D053647:Receptors, Interleukin-15; D020395:Receptors, Interleukin-7; D011993:Recombinant Fusion Proteins