title: CD4⁺CD73⁺ T cells are associated with lower T-cell activation and C reactive protein levels and are depleted in HIV-1 infection regardless of viral suppression.
abstract: BACKGROUND
  The role of the adenosine (ADO) suppression pathway, specifically CD39-expressing and CD73-expressing CD4⁺ T cells in HIV-1 infection is unclear.
  
  
  METHODS
  We evaluated the frequency and numbers of CD4⁺CD39⁺ and CD4⁺CD73⁺ T cells, activated T cells, and plasma C reactive protein (CRP) levels in 36 HIV-1-positive individuals and 10 normal controls (NC). Low-level plasma viremia was evaluated using single copy assay. Mass spectrometry was used to measure hydrolysis of ATP by ectoenzyme-expressing CD4⁺ T cells, whereas cyclic adenosine monophosphate (cAMP) levels were measured using enzyme immunoassay. Suppression of T-cell function by exogenous ADO and CD4⁺CD73⁺ T cells was tested by flow cytometry.
  
  
  RESULTS
  CD39 and CD73 are expressed in different CD4⁺ T-cell subsets. CD4⁺CD73⁺ T cells do not express CD25 and FOXP3, and their frequency and numbers were lower in HIV-1-positive individuals regardless of virologic suppression (P=0.005 and P<0.001, respectively). CD4⁺CD73⁺ numbers inversely correlated with CD4⁺CD38⁺DR⁺ (P=0.002), CD8⁺CD38⁺DR⁺ T-cell frequency (P=0.05), and plasma CRP levels (P=0.01). Both subsets are required for hydrolysis of exogenous ATP to ADO and can increase CD4⁺ T-cell cAMP levels when incubated with exogenous ATP. Low-level viremia did not correlate with activated T-cell frequency. In vitro, ADO suppressed T-cell activation and cytokine expression. CD4⁺CD7⁺ T cells suppressed T-cell proliferation only in the presence of exogenous 5'-AMP.
  
  
  CONCLUSIONS
  The ADO-producing CD4⁺CD73⁺ subset of T cells is depleted in HIV-1-positive individuals regardless of viral suppression and may play a key role in controlling HIV-1-associated immune activation.
authors.affiliation: Department of Pathology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Schuler
authors.forename: Bernard J C
authors.initials: BJ
authors.lastname: Macatangay
authors.forename: Zenichiro
authors.initials: Z
authors.lastname: Saze
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Jackson
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Riddler
authors.forename: William G
authors.initials: WG
authors.lastname: Buchanan
authors.forename: Benedict B
authors.initials: BB
authors.lastname: Hilldorfer
authors.forename: John W
authors.initials: JW
authors.lastname: Mellors
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Whiteside
authors.forename: Charles R
authors.initials: CR
authors.lastname: Rinaldo
mesh_terms: D015720:5'-Nucleotidase / Q000276:immunology / Q000378:metabolism; D000241:Adenosine / Q000378:metabolism; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D001081:Apyrase / Q000276:immunology / Q000378:metabolism; D001681:Biological Assay / Q000379:methods; D002097:C-Reactive Protein / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D016022:Case-Control Studies; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism*; D015497:HIV-1 / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation; D013058:Mass Spectrometry; D008875:Middle Aged
chemical_list: D015703:Antigens, CD; D002097:C-Reactive Protein; D015720:5'-Nucleotidase; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine