title: Increased bone marrow interleukin-7 (IL-7)/IL-7R levels but reduced IL-7 responsiveness in HIV-positive patients lacking CD4+ gain on antiviral therapy.
abstract: BACKGROUND
  The bone marrow (BM) cytokine milieu might substantially affect T-lymphocyte homeostasis in HIV-positive individuals. Interleukin-7 (IL-7) is a bone marrow-derived cytokine regulating T-cell homeostasis through a CD4+-driven feedback loop. CD4+ T-lymphopenia is associated with increased free IL-7 levels and reduced IL-7R expression/function, which are only partially reverted by highly active antiretroviral therapy (HAART). We investigated the BM production, peripheral expression and signaling (pStat5+ and Bcl-2+ CD4+/CD8+ T cells) of IL-7/IL-7Rα in 30 HAART-treated HIV-positive patients who did not experience CD4+ recovery (CD4+ ≤200/µl) and who had different levels of HIV viremia; these patients included 18 immunological nonresponders (INRs; HIV-RNA≤50), 12 complete failures (CFs; HIV-RNA>1000), and 23 HIV-seronegative subjects.
  
  
  METHODS
  We studied plasma IL-7 levels, IL-7Rα+CD4+/CD8+ T-cell proportions, IL-7Rα mRNA expression in PBMCs, spontaneous IL-7 production by BM mononuclear cells (BMMCs), and IL-7 mRNA/IL-7Rα mRNA in BMMC-derived stromal cells (SCs). We also studied T-cell responsiveness to IL-7 by measuring the proportions of pStat5+ and Bcl-2+ CD4+/CD8+ T cells.
  
  
  RESULTS
  Compared to HIV-seronegative controls, CFs and INRs presented elevated plasma IL-7 levels and lower IL-7Rα CD4+/CD8+ cell-surface expression and peripheral blood production, confirming the most relevant IL-7/IL-7R disruption. Interestingly, BM investigation revealed a trend of higher spontaneous IL-7 production in INRs (p = .09 vs. CFs) with a nonsignificant trend toward higher IL-7-Rα mRNA levels in BMMC-derived stromal cells. However, upon IL-7 stimulation, the proportion of pStat5+CD4+ T cells did not increase in INRs despite higher constitutive levels (p = .06); INRs also displayed lower Bcl-2+CD8+ T-cell proportions than controls (p = .04).
  
  
  CONCLUSIONS
  Despite severe CD4+ T-lymphopenia and a disrupted IL-7/IL-7R profile in the periphery, INRs display elevated BM IL-7/IL-7Rα expression but impaired T-cell responsiveness to IL-7, suggesting the activity of a central compensatory pathway targeted to replenish the CD4+ compartment, which is nevertheless inappropriate to compensate the dysfunctional signaling through IL-7 receptor.
authors.affiliation: Department of Medicine, Surgery and Dentistry, Clinic of Infectious Diseases, San Paolo Hospital, University of Milan, Milan, Italy.
authors.forename: Giusi Maria
authors.initials: GM
authors.lastname: Bellistrì
authors.forename: Anna
authors.initials: A
authors.lastname: Casabianca
authors.forename: Esther
authors.initials: E
authors.lastname: Merlini
authors.forename: Chiara
authors.initials: C
authors.lastname: Orlandi
authors.forename: Giulio
authors.initials: G
authors.lastname: Ferrario
authors.forename: Luca
authors.initials: L
authors.lastname: Meroni
authors.forename: Massimo
authors.initials: M
authors.lastname: Galli
authors.forename: Mauro
authors.initials: M
authors.lastname: Magnani
authors.forename: Antonella d'Arminio
authors.initials: Ad
authors.lastname: Monforte
authors.forename: Giulia
authors.initials: G
authors.lastname: Marchetti
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D005260:Female; D015658:HIV Infections / Q000097:blood*; D006679:HIV Seropositivity; D006801:Humans; D015851:Interleukin-7 / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D020395:Receptors, Interleukin-7 / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology*
chemical_list: D000998:Antiviral Agents; D015851:Interleukin-7; D020395:Receptors, Interleukin-7; D050799:STAT5 Transcription Factor