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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

Schuler, Patrick J.a,b; Macatangay, Bernard J.C.c; Saze, Zenichiroa; Jackson, Edwin K.d; Riddler, Sharon A.c; Buchanan, William G.e; Hilldorfer, Benedict B.c; Mellors, John W.c; Whiteside, Theresa L.a; Rinaldo, Charles R.e

doi: 10.1097/QAD.0b013e328360c7f3
Basic Science

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.

aDepartments of Pathology, Immunology and Otolaryngology, University of Pittsburgh Cancer Institute and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

bHals-Nasen-Ohrenklinik, Universität Duisburg-Essen, Essen, Germany

cDivision of Infectious Diseases

dDepartment of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine

eDepartment of Infectious Diseases and Microbiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA.

Correspondence to Bernard J.C. Macatangay, MD, Division of Infectious Diseases/HIV/AIDS Program, University of Pittsburgh School of Medicine, Suite 510 Keystone Building, 3520 Fifth Avenue, Pittsburgh, PA 15213, USA. Tel: +1 412 383 1272; fax: +1 412 383 2900; e-mail: macatangaybj@upmc.edu

Received 27 September, 2012

Revised 15 February, 2013

Accepted 1 March, 2013

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© 2013 Lippincott Williams & Wilkins, Inc.