title: Inflammation Perturbs the IL-7 Axis, Promoting Senescence and Exhaustion that Broadly Characterize Immune Failure in Treated HIV Infection.
abstract: BACKGROUND
  HIV-infected patients who fail to normalize CD4 T cells despite suppressive antiretroviral therapy have impaired immune homeostasis: diminished naive T-cell numbers, elevated T-cell turnover, senescence, and inflammation.
  
  
  METHODS
  Blood samples from immune failures (n = 60), immune successes (n = 20), and healthy controls (n = 20) were examined for plasma interleukin (IL)-7 levels, for cellular expression of the IL-7Rα chain (CD127), for the exhaustion and senescence markers programed death 1 (PD-1) and CD57, and for the survival factor Bcl2. Because both inflammatory and homeostatic cytokines can induce T-cell cycling, we also examined the effects of these mediators on exhaustion and senescence markers.
  
  
  RESULTS
  Plasma levels of IL-7 were elevated and both CD4 and CD8 T-cell CD127 expression was decreased in immune failure. Plasma levels of IL-7 correlated directly with naive CD4 T-cell counts in immune success and inversely with T-cell cycling (Ki67) in healthy controls and immune success, but not in immune failure. CD4 T-cell density of PD-1 was increased and Bcl2+ CD4 T cells were decreased in immune failure but not in immune success, whereas the proportion of T cells expressing CD57 was increased in immune failure. PD-1 and CD57 were induced on CD4 but not CD8 T cells by stimulation in vitro with inflammatory IL-1β or homeostatic (IL-7) cytokines.
  
  
  CONCLUSIONS
  Perturbation of the IL-7/IL-7 receptor axis, increased T-cell turnover, and increased senescence may reflect dysregulated responses to both homeostatic and inflammatory cytokines in immune failure patients.
authors.affiliation: *Department of Medicine, Division of Infectious Diseases, Center for AIDS Research, Case Western Reserve University, Cleveland, OH; †National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; ‡School of Health and Rehabilitation Sciences, The Ohio State University, Columbus, OH; §University Hospitals Case Medical Center, Cleveland, OH; and ‖Cleveland Clinic Foundation, Cleveland, OH.
authors.forename: Carey L
authors.initials: CL
authors.lastname: Shive
authors.forename: Brian
authors.initials: B
authors.lastname: Clagett
authors.forename: Marie R
authors.initials: MR
authors.lastname: McCausland
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Mudd
authors.forename: Nicholas T
authors.initials: NT
authors.lastname: Funderburg
authors.forename: Michael L
authors.initials: ML
authors.lastname: Freeman
authors.forename: Souheil-Antoine
authors.initials: SA
authors.lastname: Younes
authors.forename: Brian M
authors.initials: BM
authors.lastname: Ferrari
authors.forename: Benigno
authors.initials: B
authors.lastname: Rodriguez
authors.forename: Grace A
authors.initials: GA
authors.lastname: McComsey
authors.forename: Leonard H
authors.initials: LH
authors.lastname: Calabrese
authors.forename: Scott F
authors.initials: SF
authors.lastname: Sieg
authors.forename: Michael M
authors.initials: MM
authors.lastname: Lederman
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents; D015415:Biomarkers / Q000378:metabolism; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018959:CD57 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016022:Case-Control Studies; D016923:Cell Death / Q000502:physiology; D016922:Cellular Senescence / Q000276:immunology; D005260:Female; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D015851:Interleukin-7 / Q000097:blood*; D053699:Interleukin-7 Receptor alpha Subunit / Q000097:blood; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D017211:Treatment Failure; D051025:bcl-Associated Death Protein / Q000097:blood
chemical_list: D019380:Anti-HIV Agents; D015415:Biomarkers; D018959:CD57 Antigens; D015851:Interleukin-7; D053699:Interleukin-7 Receptor alpha Subunit; D051025:bcl-Associated Death Protein