title: Defective interleukin-2-dependent STAT5 signalling in CD8 T lymphocytes from HIV-positive patients: restoration by antiretroviral therapy.
abstract: BACKGROUND
  CD8 T lymphocytes are critical in the control of HIV replication and disease progression. Our previous studies demonstrated that CD8 T cells from chronically infected patients with high virus load proliferated poorly in response to interleukin-2 (IL-2), a cytokine critical in CD8 T cell growth and differentiation, even though relatively high levels of IL-2 receptor (IL-2R) were expressed. This suggested that signal transduction defects in response to IL-2 might be involved. The STAT5 transcription factor is important in IL-2-dependent biological responses and it is known that there are defects in unstimulated CD3 and CD4 cells in HIV-infected patients.
  
  
  OBJECTIVE
  To investigate whether the induction of STAT5 by IL-2 is altered in the CD8 T cells from HIV-positive individuals and the impact of highly active antiretroviral therapy (HAART) on its status.
  
  
  METHODS
  CD8 T lymphocytes were purified from the peripheral blood mononuclear cells of HIV-positive patients before and after HAART. Ex vivo IL-2-induced STAT5 activation was evaluated by immunoblotting and electrophoretic mobility shift assays.
  
  
  RESULTS
  CD8 T cells from a subset of untreated HIV-positive patients were unable to activate STAT5a and STAT5b proteins functionally in response to IL-2. This defect was not a result of alterations in IL-2R expression but correlated with an impaired activation of the upstream kinase Jak-3, known to mediate STAT5 activation. Overall, HAART restored Jak/STAT signalling in such patients.
  
  
  CONCLUSIONS
  These results further uncover a potential mechanism by which CD8 T cell function is impaired in HIV-infected patients.
authors.affiliation: Unit of Cellular Immunogenetics, Institut Pasteur, Paris.
authors.forename: Marko
authors.initials: M
authors.lastname: Kryworuchko
authors.forename: Virginie
authors.initials: V
authors.lastname: Pasquier
authors.forename: Hélène
authors.initials: H
authors.lastname: Keller
authors.forename: Denis
authors.initials: D
authors.lastname: David
authors.forename: Cécile
authors.initials: C
authors.lastname: Goujard
authors.forename: Jacques
authors.initials: J
authors.lastname: Gilquin
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Viard
authors.forename: Marcel
authors.initials: M
authors.lastname: Joussemet
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Delfraissy
authors.forename: Jacques
authors.initials: J
authors.lastname: Thèze
mesh_terms: D023241:Antiretroviral Therapy, Highly Active; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000276:immunology*; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology*; D053616:Janus Kinase 3; D008894:Milk Proteins; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000097:blood; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D015534:Trans-Activators / Q000276:immunology*; D025521:Tumor Suppressor Proteins
chemical_list: D004268:DNA-Binding Proteins; D007376:Interleukin-2; D008894:Milk Proteins; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3