{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T15:03:26Z","timestamp":1781708606757,"version":"3.54.5"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T00:00:00Z","timestamp":1623283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Targeting immune checkpoints for HIV treatment potentially provides a double benefit resulting from the ability to restore viral-specific CD8<jats:sup>+<\/jats:sup> T-cell functions and enhance HIV production from reservoir cells. Despite promising pre-clinical data, PD-1 blockade alone in HIV-1-infected patients with advanced cancer has shown limited benefits in controlling HIV, suggesting the need for additional targets beyond PD-1. CD39 and PD-1 are highly co-expressed on CD8<jats:sup>+<\/jats:sup> T cells in HIV-1 infection. However, the characteristics of CD39 and PD-1 dual-positive CD8<jats:sup>+<\/jats:sup> T-cell subsets in chronic HIV-1 infection remain poorly understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This study enrolled 72 HIV-1-infected patients, including 40 treatment na\u00efve and 32 ART patients. A total of 11 healthy individuals were included as controls. Different subsets of CD8<jats:sup>+<\/jats:sup> T cells defined by CD39 and\/or PD-1 expression were studied by flow cytometry. The relationships between the frequencies of the different subsets and parameters indicating HIV-1 disease progression were analyzed. Functional (i.e., cytokine secretion, viral inhibition) assays were performed to evaluate the impact of the blockade of adenosine and\/or PD-1 signaling on CD8<jats:sup>+<\/jats:sup> T cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The proportions of PD-1<jats:sup>+<\/jats:sup>, CD39<jats:sup>+<\/jats:sup>, and PD-1<jats:sup>+<\/jats:sup>CD39<jats:sup>+<\/jats:sup> CD8<jats:sup>+<\/jats:sup> T cells were significantly increased in treatment na\u00efve patients but were partially lowered in patients on antiretroviral therapy. In treatment na\u00efve patients, the proportions of PD-1<jats:sup>+<\/jats:sup>CD39<jats:sup>+<\/jats:sup> CD8<jats:sup>+<\/jats:sup> T cells were negatively correlated with CD4<jats:sup>+<\/jats:sup> T-cell counts and the CD4\/CD8 ratio, and were positively correlated with viral load. CD39<jats:sup>+<\/jats:sup>CD8<jats:sup>+<\/jats:sup> T cells expressed high levels of the A2A adenosine receptor and were more sensitive to 2-chloroadenosine-mediated functional inhibition than their CD39<jats:sup>-<\/jats:sup> counterparts. <jats:italic>In vitro<\/jats:italic>, a combination of blocking CD39\/adenosine and PD-1 signaling showed a synergic effect in restoring CD8<jats:sup>+<\/jats:sup> T-cell function, as evidenced by enhanced abilities to secrete functional cytokines and to kill autologous reservoir cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In patients with chronic HIV-1 infection there are increased frequencies of PD-1<jats:sup>+<\/jats:sup>, CD39<jats:sup>+<\/jats:sup>, and PD-1<jats:sup>+<\/jats:sup>CD39<jats:sup>+<\/jats:sup> CD8<jats:sup>+<\/jats:sup> T cells. In treatment na\u00efve patients, the frequencies of PD-1<jats:sup>+<\/jats:sup>CD39<jats:sup>+<\/jats:sup> CD8<jats:sup>+<\/jats:sup> T cells are negatively correlated with CD4<jats:sup>+<\/jats:sup> T-cell counts and the CD4\/CD8 ratio and positively correlated with viral load. Combined blockade of CD39\/adenosine and PD-1 signaling <jats:italic>in vitro<\/jats:italic> may exert a synergistic effect in restoring CD8<jats:sup>+<\/jats:sup> T-cell function in HIV-1-infected patients.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2021.687296","type":"journal-article","created":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T04:58:32Z","timestamp":1623301112000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":27,"title":["Reversal of the CD8+ T-Cell Exhaustion Induced by Chronic HIV-1 Infection Through Combined Blockade of the Adenosine and PD-1 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