title: HIV infection perturbs interleukin-7 signaling at the step of STAT5 nuclear relocalization.
abstract: OBJECTIVE
  Interleukin-7 (IL-7) responses are impaired in CD4(+) T cells from HIV-infected patients, which may play a significant role in the loss of CD4(+) T-cell homeostasis. We set to investigate the nature of IL-7-dependent signaling defects in patients with progressive HIV-1 infection.
  
  
  METHODS
  IL-7 signaling was compared in CD4(+) T cells from viremic patients with a viral load more than 10,000 copies of HIV RNA/ml (n = 23) and from healthy blood donors (n = 23). Phosphorylation of the transcription factor STAT5 on the regulatory serine S726 and the key tyrosine Y694 was monitored by intracellular flow cytometry. Phospho-STAT5 relocalization to the nucleus was analyzed by quantitative immunofluorescence imaging.
  
  
  RESULTS
  In control CD4(+) T cells, S726 phosphorylation was mostly constitutive and inducible by IL-7 to a limited extent (1.3x, P < 0.05). In contrast, phosphorylation at Y694 was highly inducible by IL-7 (12.6x, P < 0.0001). Progressive HIV infection led to hyperphosphorylation of both S726 and Y694 in naive CD4(+) T cells, with these changes correlating together (R = 0.66, P = 0.01). Quantitative image analysis revealed an impairment in the nuclear relocalization of both forms of phospho-STAT5 in patient cells (P < 0.005 for S726; P < 0.05 for Y694). The nuclear relocalization defect correlated with increased HLA-DR expression (R = 0.75, P < 0.01), suggesting a role for chronic immune activation in perturbed IL-7 signal transduction.
  
  
  CONCLUSIONS
  HIV infection perturbs IL-7 signaling by impairing the access of STAT5 to the nuclear compartment. This defect may contribute to the loss of CD4(+) T-cell populations in patients with chronically high immune activation.
authors.affiliation: Pasteur Institute, Cellular Immunogenetics Unit, Paris, France.
authors.forename: Ivan
authors.initials: I
authors.lastname: Landires
authors.forename: Florence
authors.initials: F
authors.lastname: Bugault
authors.forename: Olivier
authors.initials: O
authors.lastname: Lambotte
authors.forename: Pierre
authors.initials: P
authors.lastname: de Truchis
authors.forename: Laurence
authors.initials: L
authors.lastname: Slama
authors.forename: Anne
authors.initials: A
authors.lastname: Danckaert
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Delfraissy
authors.forename: Jacques
authors.initials: J
authors.lastname: Thèze
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Chakrabarti
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D015851:Interleukin-7 / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D019562:Viral Load; D014766:Viremia / Q000276:immunology
chemical_list: D015851:Interleukin-7; D050799:STAT5 Transcription Factor