{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T03:34:10Z","timestamp":1781148850289,"version":"3.54.1"},"reference-count":82,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2022,3,24]],"date-time":"2022-03-24T00:00:00Z","timestamp":1648080000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["353953"],"award-info":[{"award-number":["353953"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CIHR New Investigator Salary Award","award":["360929"],"award-info":[{"award-number":["360929"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>CD8<jats:sup>+<\/jats:sup> T cells play a crucial role against chronic viral infections, however, their effector functions are influenced by the expression of co-stimulatory\/inhibitory receptors. For example, CD73 works with CD39 to convert highly inflammatory ATP to adenosine. However, its expression on T cells in the context of viral infections has not been well defined. Here, we analyzed the expression of CD73 on human T cells in a cohort of 102 HIV-infected individuals including those on antiretroviral therapy (ART), ART-na\u00efve, and long-term non-progressors who were not on ART. We found that the frequency of CD73<jats:sup>+<\/jats:sup> T cells was markedly lower among T cell subsets (e.g. na\u00efve, effector or memory) in the peripheral blood of all HIV-infected individuals. Notably, CD73 was decreased at the cell surface, intracellular and gene levels. Functionally, CD8<jats:sup>+<\/jats:sup>CD73<jats:sup>+<\/jats:sup> T cells exhibited decreased cytokine expression (TNF-\u03b1, IFN-\u03b3 and IL-2) upon global or antigen-specific stimulation and impaired expression of cytolytic molecules at the gene and protein levels. In contrast, CD8<jats:sup>+<\/jats:sup>CD73<jats:sup>+<\/jats:sup> T cells expressed elevated levels of homing receptors such as CCR7, \u03b14\u03b27 integrin, which suggests a migratory advantage for these cells as observed <jats:italic>in vitro<\/jats:italic>. We also observed significant migration of CD73<jats:sup>+<\/jats:sup>CD8<jats:sup>+<\/jats:sup> T cells into the cerebrospinal fluids of multiple sclerosis (MS) patients at the time of disease relapse. Moreover, we found that elevated levels of ATP in the plasma of HIV-infected individuals upregulates the expression of miRNA30b-e in T cells <jats:italic>in vitro<\/jats:italic>. In turn, inhibition of miRNAs (30b, 30c and 30e) resulted in significant upregulation of CD73 mRNA in CD8<jats:sup>+<\/jats:sup> T cells. Therefore, we provide a novel mechanism for the downregulation of CD73 via ATP-induced upregulation of miRNA30b, 30c and 30e in HIV infection. Finally, these observations imply that ATP-mediated downregulation of CD73 mainly occurs via its receptor, P2X1\/P2RX1. Our results may in part explain why HIV-infected individuals have reduced risk of developing MS considering the role of CD73 for efficient T cell entry into the central nervous system.<\/jats:p>","DOI":"10.1371\/journal.ppat.1010378","type":"journal-article","created":{"date-parts":[[2022,3,24]],"date-time":"2022-03-24T21:51:31Z","timestamp":1648158691000},"page":"e1010378","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":26,"title":["Elevated ATP via enhanced miRNA-30b, 30c, and 30e downregulates the expression of CD73 in CD8+ T cells of HIV-infected individuals"],"prefix":"10.1371","volume":"18","author":[{"given":"Shima","family":"Shahbaz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isobel","family":"Okoye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregg","family":"Blevins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7215-2009","authenticated-orcid":true,"given":"Shokrollah","family":"Elahi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,3,24]]},"reference":[{"issue":"10","key":"ppat.1010378.ref001","doi-asserted-by":"crossref","first-page":"633","DOI":"10.4330\/wjc.v7.i10.633","article-title":"Cardiovascular disease in human immunodeficiency virus infected patients: A true or perceived risk?","volume":"7","author":"S Shahbaz","year":"2015","journal-title":"World J Cardiol."},{"issue":"9903","key":"ppat.1010378.ref002","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1016\/S0140-6736(13)61809-7","article-title":"The end of AIDS: HIV infection as a chronic disease","volume":"382","author":"SG Deeks","year":"2013","journal-title":"Lancet"},{"issue":"2","key":"ppat.1010378.ref003","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1097\/QAD.0000000000000917","article-title":"Atorvastatin restricts HIV replication in CD4+ T cells by upregulation of p21","volume":"30","author":"S Elahi","year":"2016","journal-title":"Aids"},{"issue":"1","key":"ppat.1010378.ref004","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1111\/imr.12079","article-title":"HIV-associated chronic immune activation","volume":"254","author":"M Paiardini","year":"2013","journal-title":"Immunol Rev"},{"issue":"22","key":"ppat.1010378.ref005","doi-asserted-by":"crossref","first-page":"3454","DOI":"10.1016\/j.febslet.2015.07.027","article-title":"CD73 and CD39 ectonucleotidases in T cell differentiation: Beyond immunosuppression","volume":"589","author":"MR Bono","year":"2015","journal-title":"FEBS Lett"},{"issue":"5","key":"ppat.1010378.ref006","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.it.2012.02.009","article-title":"CD73: a potent suppressor of antitumor immune responses","volume":"33","author":"PA Beavis","year":"2012","journal-title":"Trends Immunol"},{"key":"ppat.1010378.ref007","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1111\/j.1600-065X.1998.tb01574.x","article-title":"Ecto-enzyme and signaling functions of lymphocyte CD73","volume":"161","author":"R Resta","year":"1998","journal-title":"Immunol Rev"},{"issue":"10","key":"ppat.1010378.ref008","doi-asserted-by":"crossref","first-page":"5411","DOI":"10.4049\/jimmunol.165.10.5411","article-title":"CD73 engagement promotes lymphocyte binding to endothelial cells via a lymphocyte function-associated antigen-1-dependent mechanism","volume":"165","author":"L Airas","year":"2000","journal-title":"Journal of immunology"},{"key":"ppat.1010378.ref009","doi-asserted-by":"crossref","first-page":"813","DOI":"10.3389\/fimmu.2018.00813","article-title":"Controlling the Immune Suppressor: Transcription Factors and MicroRNAs Regulating CD73\/NT5","volume":"9","author":"T Kordass","year":"2018","journal-title":"E. 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