CD39/Adenosine Pathway Is Involved in AIDS Progression

Abstract

HIV-1 infection is characterized by a chronic activation of the immune system and suppressed function of T lymphocytes. Regulatory CD4+ CD25high FoxP3+CD127low T cells (Treg) play a key role in both conditions. Here, we show that HIV-1 positive patients have a significant increase of Treg-associated expression of CD39/ENTPD1, an ectoenzyme which in concert with CD73 generates adenosine. We show in vitro that the CD39/adenosine axis is involved in Treg suppression in HIV infection. Treg inhibitory effects are relieved by CD39 down modulation and are reproduced by an adenosine-agonist in accordance with a higher expression of the adenosine A2A receptor on patients' T cells. Notably, the expansion of the Treg CD39+ correlates with the level of immune activation and lower CD4+ counts in HIV-1 infected patients. Finally, in a genetic association study performed in three different cohorts, we identified a CD39 gene polymorphism that was associated with down-modulated CD39 expression and a slower progression to AIDS.

Human antigen‐specific CD4+CD25+CD134+CD39+ T cells are enriched for regulatory T cells and comprise a substantial proportion of recall responses

“…This supports previous studies where CD39, in combination with other Treg-cell surface markers, identified a population of human FOXP3 + suppressive Treg cells [11,14,43,44].…”

“…In humans, approximately 60% of ex vivo CD4 + FOXP3 + Treg cells express CD39, however very little cell surface expression of CD73 is observed [11][12][13]. Although CD39 surface expression on CD4 + T cells allows characterisation of bulk populations of Treg cells, it does not allow interrogation of Ag specificity.In clinical settings of autoimmune disease and chronic infection, CD39 + Treg cells are an important cell subset and disease correlations have been found with alterations in their phenotype and function [11,12,14,15]. In multiple sclerosis, it has been shown that although CD39 + Treg cells are able to suppress pathogenic Th17 cells [12], their frequencies are significantly reduced compared with healthy controls [11].…”

Homeostasis and Function of Regulatory T Cells in HIV/SIV Infection

“…However, whether all these mechanisms act individually or synergistically, as well as whether their efficacy is different in different compartments, is not yet clear. (19,63). The majority of studies with patients who were HIV-infected long-term nonprogressors (LTNP) or elite controllers reported decreases in Treg frequencies in peripheral blood (68,80,82) and rectal mucosa (82) in these individuals compared to that in progressors.…”

“…Ex vivo depletion of Tregs from peripheral blood mononuclear cells (PBMCs) or lymphoid cell suspensions enhances T cell responses to HIV or SIV antigens (1,35,41,44,63,96). (Fig.…”

“…In addition to their role in controlling peripheral tolerance, Tregs promote the establishment of multiple persistent infections (viral, bacterial, parasitic, and fungal) (reviewed in reference 10). In most studies, Treg frequency was found to be substantially increased during the chronic phase of HIV infection (4,7,12,19,28,63,65,71,80,82,96). Thus, Tregs may contribute substantially to inefficient CMI during HIV infection.…”