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

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(+)CD73(+) T cells suppressed T-cell proliferation only in the presence of exogenous 5-AMP.Conclusion: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.